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Cardiac hypertrophy is a common feature in several cardiomyopathies. We previously reported that loss of ADAM15 (disintegrin and metalloproteinase 15) worsened cardiac hypertrophy and dilated cardiomyopathy following cardiac pressure overload. Here, we investigated the impact of ADAM15 loss in female mice following cardiac pressure overload induced by transverse aortic constriction (TAC). Female Adam15−/− mice developed the same degree of cardiac hypertrophy, dilation, and dysfunction as the parallel female wild-type (WT) mice at 6 wk post-TAC. To determine if this is due to the protective effects of estrogen, which could mask the negative impact of Adam15 loss, WT and Adam15−/− mice underwent ovariectomy (OVx) 2 wk before TAC. Cardiac structure and function analyses were performed at 6 wk post-TAC. OVx similarly impacted females of both genotypes post-TAC. Calcineurin (Cn) activity was increased post-OVx-TAC, and more in Adam15−/− mice; however, this increase was not reflected in the total-to-phospho-NFAT levels. Integrin-α7 expression, which was upstream of Cn activation in male Adam15−/− -TAC mice, remained unchanged in female mice. However, activation of the mitogen-activated protein kinases (ERK, JNK, P38) was greater in Adam15−/−-OVx-TAC than in WT-OVx-TAC mice. In addition, ADAM15 protein levels were significantly increased post-TAC in male but not in female WT mice. Myocardial fibrosis was comparable in non-OVx WT-TAC and Adam15−/− -TAC mice. OVx increased the perivascular fibrosis more in Adam15−/− compared with WT mice post-TAC. Our data demonstrate that loss of ovarian hormones did not fully replicate the male phenotype in the female Adam15−/− mice post-TAC. As ADAM15 levels were increased in males but not in females post-TAC, it is plausible that ADAM15 does not play a prominent role in post-TAC events in female mice. Our findings highlight the significance of factors other than sex hormones in mediating cardiomyopathies in females, which require a more thorough understanding. NEW & NOTEWORTHY: Loss of ADAM15 in female mice, unlike the male mice, does not worsen the cardiomyopathy following cardiac pressure overload. Ovariectomy does not worsen the post-TAC cardiomyopathy in female Adam15−/− mice compared with female WT mice. Lack of deleterious impact of Adam15 deficiency in female mice is not because of the protective effects of ovarian hormones but could be due to a less prominent role of ADAM15 in cardiac response to post-TAC remodeling in female mice. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes (T2D) is a frequent comorbidity encountered in patients with severe aortic stenosis (AS), leading to an adverse left ventricular (LV) remodeling and dysfunction. Metabolic alterations have been suggested as contributors of the deleterious effect of T2D on LV remodeling and function in patients with severe AS, but so far, the underlying mechanisms remain unclear. Mitochondria play a central role in the regulation of cardiac energy metabolism. Objectives: We aimed to explore the mitochondrial alterations associated with the deleterious effect of T2D on LV remodeling and function in patients with AS, preserved ejection fraction, and no additional heart disease. Methods: We combined an in-depth clinical, biological and echocardiography phenotype of patients with severe AS, with (n = 34) or without (n = 50) T2D, referred for a valve replacement, with transcriptomic and histological analyses of an intra-operative myocardial LV biopsy. Results: T2D patients had similar AS severity but displayed worse cardiac remodeling, systolic and diastolic function than non-diabetics. RNAseq analysis identified 1029 significantly differentially expressed genes. Functional enrichment analysis revealed several T2D-specific upregulated pathways despite comorbidity adjustment, gathering regulation of inflammation, extracellular matrix organization, endothelial function/angiogenesis, and adaptation to cardiac hypertrophy. Downregulated gene sets independently associated with T2D were related to mitochondrial respiratory chain organization/function and mitochondrial organization. Generation of causal networks suggested a reduced Ca2+ signaling up to the mitochondria, with the measured gene remodeling of the mitochondrial Ca2+ uniporter in favor of enhanced uptake. Histological analyses supported a greater cardiomyocyte hypertrophy and a decreased proximity between the mitochondrial VDAC porin and the reticular IP3-receptor in T2D. Conclusions: Our data support a crucial role for mitochondrial Ca2+ signaling in T2D-induced cardiac dysfunction in severe AS patients, from a structural reticulum-mitochondria Ca2+ uncoupling to a mitochondrial gene remodeling. Thus, our findings open a new therapeutic avenue to be tested in animal models and further human cardiac biopsies in order to propose new treatments for T2D patients suffering from AS. Trial registration: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT01862237. [ABSTRACT FROM AUTHOR]

Abstract Background Type 2 diabetes (T2D) is a frequent comorbidity encountered in patients with severe aortic stenosis (AS), leading to an adverse left ventricular (LV) remodeling and dysfunction. Metabolic alterations have been suggested as contributors of the deleterious effect of T2D on LV remodeling and function in patients with severe AS, but so far, the underlying mechanisms remain unclear. Mitochondria play a central role in the regulation of cardiac energy metabolism. Objectives We aimed to explore the mitochondrial alterations associated with the deleterious effect of T2D on LV remodeling and function in patients with AS, preserved ejection fraction, and no additional heart disease. Methods We combined an in-depth clinical, biological and echocardiography phenotype of patients with severe AS, with (n = 34) or without (n = 50) T2D, referred for a valve replacement, with transcriptomic and histological analyses of an intra-operative myocardial LV biopsy. Results T2D patients had similar AS severity but displayed worse cardiac remodeling, systolic and diastolic function than non-diabetics. RNAseq analysis identified 1029 significantly differentially expressed genes. Functional enrichment analysis revealed several T2D-specific upregulated pathways despite comorbidity adjustment, gathering regulation of inflammation, extracellular matrix organization, endothelial function/angiogenesis, and adaptation to cardiac hypertrophy. Downregulated gene sets independently associated with T2D were related to mitochondrial respiratory chain organization/function and mitochondrial organization. Generation of causal networks suggested a reduced Ca2+ signaling up to the mitochondria, with the measured gene remodeling of the mitochondrial Ca2+ uniporter in favor of enhanced uptake. Histological analyses supported a greater cardiomyocyte hypertrophy and a decreased proximity between the mitochondrial VDAC porin and the reticular IP3-receptor in T2D. Conclusions Our data support a crucial role for mitochondrial Ca2+ signaling in T2D-induced cardiac dysfunction in severe AS patients, from a structural reticulum-mitochondria Ca2+ uncoupling to a mitochondrial gene remodeling. Thus, our findings open a new therapeutic avenue to be tested in animal models and further human cardiac biopsies in order to propose new treatments for T2D patients suffering from AS. Trial registration URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT01862237. Graphical abstract

Abstract Pathological cardiac hypertrophy is an important cause of heart failure(HF). Recent studies reveal that glucagon-like peptide-1 receptor (GLP1R) agonists can improve mortality and left ventricular ejection fraction in the patients with type 2 diabetes and HF. The present study aims to investigate whether semaglutide, a long-acting GLP1R agonist, can ameliorate cardiac hypertrophy induced by pressure overload, and explore the potential mechanism. The rats were performed transverse aortic constriction (TAC) to mimic pressure overload model. The rats were divided into four groups including Sham, TAC, TAC + semaglutide, and TAC + semaglutide + HCQ (hydroxychloroquine, an inhibitor of mitophagy). The rats in each experimental group received their respective interventions for 4 weeks. The parameters of left ventricular hypertrophy(LVH) were measured by echocardiography, Hematoxylin–eosin (HE) staining, western-blot and immunohistochemistry (IHC), respectively. The changes of mitophagy were reflected by detecting cytochrome c oxidase subunit II (COXII), LC3II/LC3I, mitochondria, and autophagosomes. Meanwhile, NLRP3, Caspase-1, and interleukin-18 were detected to evaluate the activation of NLRP3 inflammasome in each group. The results suggest that LVH, impaired mitophagy, and activation of NLRP3 inflammasome were present in TAC rats. Semaglutide significantly reduced LVH, improve mitophagy, and down-regulated NLRP3 inflammatory signal pathway in TAC rats. However, the reversed effect of semaglutide on cardiac hypertrophy was abolished by HCQ, which restored the activation of NLRP3 inflammasome suppressed by improved mitophagy. In conclusion, semaglutide ameliorates the cardiac hypertrophy by improving cardiac mitophagy to suppress the activation of NLRP3 inflammasome. Semaglutide may be a novel potential option for intervention of cardiac hypertrophy induced by pressure overload.

Brown adipose tissue (BAT) is correlated to cardiovascular health in rodents and humans, but the physiological role of BAT in the initial cardiac remodeling at the onset of stress is unknown. Activation of BAT via 48 h cold (16°C) in mice following transverse aortic constriction (TAC) reduced cardiac gene expression for LCFA uptake and oxidation in male mice and accelerated the onset of cardiac metabolic remodeling, with an early isoform shift of carnitine palmitoyltransferase 1 (CPT1) toward increased CPT1a, reduced entry of long chain fatty acid (LCFA) into oxidative metabolism (0.59 ± 0.02 vs. 0.72 ± 0.02 in RT TAC hearts, p <.05) and increased carbohydrate oxidation with altered glucose transporter content. BAT activation with TAC reduced early hypertrophic expression of β‐MHC by 61% versus RT‐TAC and reduced pro‐fibrotic TGF‐β1 and COL3α1 expression. While cardiac natriuretic peptide expression was yet to increase at only 3 days TAC, Nppa and Nppb expression were elevated in Cold TAC versus RT TAC hearts 2.7‐ and 2.4‐fold, respectively. Eliminating BAT thermogenic activation with UCP1 KO mice eliminated differences between Cold TAC and RT TAC hearts, confirming effects of BAT activation rather than autonomous cardiac responses to cold. Female responses to BAT activation were blunted, with limited UCP1 changes with cold, partly due to already activated BAT in females at RT compared to thermoneutrality. These data reveal a previously unknown physiological mechanism of UCP1‐dependent BAT activation in attenuating early cardiac hypertrophic and profibrotic signaling and accelerating remodeled metabolic activity in the heart at the onset of cardiac stress. [ABSTRACT FROM AUTHOR]

Valvular heart disease leads to ventricular pressure and/or volume overload. Pressure overload leads to fibrosis, which might regress with its resolution, but the limits and details of this reverse remodeling are not known. To gain more insight into the extent and nature of cardiac fibrosis in valve disease, we analyzed needle biopsies taken from the interventricular septum of patients undergoing surgery for valve replacement focusing on the expression and distribution of major extracellular matrix protein involved in this process. Proteomic analysis performed using mass spectrometry revealed an excellent correlation between the expression of collagen type I and III, but there was little correlation with the immunohistochemical staining performed on sister sections, which included antibodies against collagen I, III, fibronectin, sarcomeric actin, and histochemistry for wheat germ agglutinin. Surprisingly, the immunofluorescence intensity did not correlate significantly with the gold standard for fibrosis quantification, which was performed using Picrosirius Red (PSR) staining, unless multiplexed on the same tissue section. There was also little correlation between the immunohistochemical markers and pressure gradient severity. It appears that at least in humans, the immunohistochemical pattern of fibrosis is not clearly correlated with standard Picrosirius Red staining on sister sections or quantitative proteomic data, possibly due to tissue heterogeneity at microscale, comorbidities, or other patient-specific factors. For precise correlation of different types of staining, multiplexing on the same section is the best approach. [ABSTRACT FROM AUTHOR]

Hypertension is a major cause of cardiovascular diseases such as myocardial infarction and stroke. Cardiovascular fibrosis occurs with hypertension and contributes to vascular resistance, aortic stiffness, and cardiac hypertrophy. However, the molecular mechanisms leading to fibroblast activation in hypertension remain largely unknown. There are two types of fibrosis: replacement fibrosis and reactive fibrosis. Replacement fibrosis occurs in response to the loss of viable tissue to form a scar. Reactive fibrosis occurs in response to an increase in mechanical and neurohormonal stress. Although both types of fibrosis are considered adaptive processes, they become maladaptive when the tissue loss is too large, or the stress persists. Myofibroblasts represent a subpopulation of activated fibroblasts that have gained contractile function to promote wound healing. Therefore, myofibroblasts are a critical cell type that promotes replacement fibrosis. Although myofibroblasts were recognized as the fibroblasts participating in reactive fibrosis, recent experimental evidence indicated there are distinct fibroblast populations in cardiovascular reactive fibrosis. Accordingly, we will discuss the updated definition of fibroblast subpopulations, the regulatory mechanisms, and their potential roles in cardiovascular pathophysiology utilizing new knowledge from various lineage tracing and single-cell RNA sequencing studies. Among the fibroblast subpopulations, we will highlight the novel roles of matrifibrocytes and immune fibrocytes in cardiovascular fibrosis including experimental models of hypertension, pressure overload, myocardial infarction, atherosclerosis, aortic aneurysm, and nephrosclerosis. Exploration into the molecular mechanisms involved in the differentiation and activation of those fibroblast subpopulations may lead to novel treatments for end-organ damage associated with hypertension and other cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Simple Summary: Abnormal hemodynamics and cardiac and pulmonary development intertwine to form the most important features of children with congenital heart diseases (CHDs). Here, we review the varieties of hemodynamic abnormalities that exist in children with CHDs and the recently developed neonatal rodent models of CHDs, which have inspired and brought us new ideas and inspirations in cardiomyocyte proliferation and maturation, as well as in alveolar development. Hemodynamics is the eternal theme of the circulatory system. Abnormal hemodynamics and cardiac and pulmonary development intertwine to form the most important features of children with congenital heart diseases (CHDs), thus determining these children's long-term quality of life. Here, we review the varieties of hemodynamic abnormalities that exist in children with CHDs, the recently developed neonatal rodent models of CHDs, and the inspirations these models have brought us in the areas of cardiomyocyte proliferation and maturation, as well as in alveolar development. Furthermore, current limitations, future directions, and clinical decision making based on these inspirations are highlighted. Understanding how CHD-associated hemodynamic scenarios shape postnatal heart and lung development may provide a novel path to improving the long-term quality of life of children with CHDs, transplantation of stem cell-derived cardiomyocytes, and cardiac regeneration. [ABSTRACT FROM AUTHOR]

Pathologic cardiac hypertrophy is a common consequence of many cardiovascular diseases, including aortic stenosis (AS). AS is known to increase the pressure load of the left ventricle, causing a compensative response of the cardiac muscle, which progressively will lead to dilation and heart failure. At a cellular level, this corresponds to a considerable increase in the size of cardiomyocytes, known as cardiomyocyte hypertrophy, while their proliferation capacity is attenuated upon the first developmental stages. Cardiomyocytes, in order to cope with the increased workload (overload), suffer alterations in their morphology, nuclear content, energy metabolism, intracellular homeostatic mechanisms, contractile activity, and cell death mechanisms. Moreover, modifications in the cardiomyocyte niche, involving inflammation, immune infiltration, fibrosis, and angiogenesis, contribute to the subsequent events of a pathologic hypertrophic response. Considering the emerging need for a better understanding of the condition and treatment improvement, as the only available treatment option of AS consists of surgical interventions at a late stage of the disease, when the cardiac muscle state is irreversible, large animal models have been developed to mimic the human condition, to the greatest extend. Smaller animal models lack physiological, cellular and molecular mechanisms that sufficiently resemblance humans and in vitro techniques yet fail to provide adequate complexity. Animals, such as the ferret (Mustello purtorius furo), lapine (rabbit, Oryctolagus cunigulus), feline (cat, Felis catus), canine (dog, Canis lupus familiaris), ovine (sheep, Ovis aries), and porcine (pig, Sus scrofa), have contributed to research by elucidating implicated cellular and molecular mechanisms of the condition. Essential discoveries of each model are reported and discussed briefly in this review. Results of large animal experimentation could further be interpreted aiming at prevention of the disease progress or, alternatively, at regression of the implicated pathologic mechanisms to a physiologic state. This review summarizes the important aspects of the pathophysiology of LV hypertrophy and the applied surgical large animal models that currently better mimic the condition. [ABSTRACT FROM AUTHOR]

Purpose: Grb2 associated binding protein 1 (Gab1) is an adaptor protein that is important for intracellular signal transduction which involved in several pathological process. However, the role of Gab1 in pressure overload-induced ventricular arrhythmias (VAs) remain poorly understood. In the current study, we aimed to test the role of Gab1 in VA susceptibility induced by pressure overload. Methods: We overexpressed Gab1 in the hearts using an adeno-associated virus 9 (AAV9) system through tail vein injection. Aortic banding (AB) surgery was performed in C57BL6/J mice to induce heart failure (HF). Four weeks following AB, histology, echocardiography, and biochemical analysis were conducted to investigate cardiac structural remodeling and electrophysiological studies were performed to check the electrical remodeling. Western blot analysis was used to explore the underlying mechanisms. Results: The mRNA and protein expression were downregulated in AB hearts compared to sham hearts. Gab1 overexpression significantly reversed AB-induced cardiac structural remodeling including ameliorated AB-induced cardiac dysfunction, cardiac fibrosis, and inflammatory response. Moreover, Gab1 overexpression also markedly alleviated AB-induced electrical remodeling including ion channel alterations and VA susceptibility. Mechanistically, we found that TLR4/MyD88/NF-κB contributes to the cardio protective effect of Gab1 overexpression on AB-induced VAs. Conclusions: Our study manifested that Gab1 may serve as a promising anti-arrhythmic target via inhibiting TLR4/MyD88/NF-κB signaling pathway induced by AB. [ABSTRACT FROM AUTHOR]

ABSTRACTHeart failure, a leading driver of global mortality, remains a topic of intense contemporary research interest due to the prevailing unmet need in cardiometabolic therapeutics. Numerous mechanisms with the potential to influence the onset and development of heart failure remain incompletely understood. Firstly, myocardial autophagy, which involves lysosomal degradation of damaged cellular components, confers context-dependent beneficial and detrimental effects. Secondly, sterile inflammation may arise following cardiac stress and exacerbate the progression of heart failure. Inflammation changes in a temporal manner and its onset must be adequately resolved to limit progression of heart failure. Mitochondria are an important factor in contributing to sterile inflammation by releasing damage associated molecular patterns (DAMPs) including mitochondrial DNA (mtDNA). Accordingly, this is one reason why the selective autophagy of mitochondria to maintain optimal function is important in determining cardiac function. In this review, we examine the increasing evidence suggesting crosstalk between autophagy and sterile inflammation together with their role in the development of heart failure. In particular, this is exemplified in the preclinical models of ischaemia/reperfusion injury and pressure overload induced heart failure. We also highlight potential therapeutic approaches focusing on autophagy and addressing sterile inflammation, aiming to enhance outcomes in heart failure.

Introduction: Thyroid hormones (THs) are known to have various effects on the cardiovascular system. However, the impact of TH levels on preexisting cardiac diseases is still unclear. Pressure overload due to arterial hypertension or aortic stenosis and aging are major risk factors for the development of structural and functional abnormalities and subsequent heart failure. Here, we assessed the sensitivity to altered TH levels in aged mice with maladaptive cardiac hypertrophy and cardiac dysfunction induced by transverse aortic constriction (TAC). Methods: Mice at the age of 12 months underwent TAC and received T4 or antithyroid medication in drinking water over the course of 4 weeks after induction of left ventricular pressure overload. Results: T4 excess or deprivation in older mice had no or only very little impact on cardiac function (fractional shortening), cardiac remodeling (cardiac wall thickness, heart weight, cardiomyocyte size, apoptosis, and interstitial fibrosis), and mortality. This is surprising because T4 excess or deprivation had significantly changed the outcome after TAC in young 8-week-old mice. Comparing the gene expression of deiodinases (Dio) 2 and 3 and TH receptor alpha (TRα) 1 and the dominant-negative acting isoform TRα2 between young and aged mice revealed that aged mice exhibited a higher expression of TRα2 and Dio3, while expression of Dio2 was reduced compared with young mice. These changes in Dio2 and 3 expressions might lead to reduced TH availability in the hearts of 12- month-old mice accompanied by reduced TRα action due to higher TRα2. Discussion: In summary, our study shows that low and high TH availability have little impact on cardiac function and remodeling in older mice with preexisting pressure-induced cardiac damage. This observation seems to be the result of an altered expression of deiodinases and TRα isoforms, thus suggesting that even though cardiovascular risk is increasing with age, the response to TH stress may be dampened in certain conditions. [ABSTRACT FROM AUTHOR]

Diseased animal models play an extremely important role in preclinical research. Lacking the corresponding animal models, many basic research studies cannot be carried out, and the conclusions obtained are incomplete or even incorrect. Right ventricular (RV) outflow tract (RVOT) obstruction leads to RV pressure overload (PO) and reduced pulmonary blood flow (RPF), which are 2 of the most important pathophysiological characteristics in pediatric cardiovascular diseases and seriously affect the survival rate and long-term quality of life of many children. Due to the lack of a neonatal mouse model for RVOT obstruction, it is largely unknown how RV PO and RPF regulate postnatal RV and pulmonary development. The aim of this study was to construct a neonatal RVOT obstruction mouse model. Here, we first introduced a neonatal mouse model of RVOT obstruction by pulmonary artery banding (PAB) on postnatal day 1. PAB induced neonatal RVOT obstruction, RV PO, and RPF. Neonatal RV PO induced cardiomyocyte proliferation, and neonatal RPF induced pulmonary dysplasia, the 2 features that are not observed in adult RVOT obstruction. As a result, PAB neonates exhibited overall developmental dysplasia, a sign similar to that of children with RVOT obstruction. Because many pediatric cardiovascular diseases are associated with RV PO and RPF, the introduction of a neonatal mouse model of RVOT obstruction may greatly enhance our understanding of these diseases and eventually improve or save the lives of many children. [Display omitted] [ABSTRACT FROM AUTHOR]

Anserine, an imidazole dipeptide, is present in the muscles of birds and fish and has various bioactivities, such as anti-inflammatory and anti-fatigue effects. However, the effect of anserine on the development of heart failure remains unknown. We cultured primary cardiomyocytes with 0.03 mM to 10 mM anserine and stimulated them with phenylephrine for 48 h. Anserine significantly suppressed the phenylephrine-induced increases in cardiomyocyte hypertrophy, ANF and BNP mRNA levels, and histone H3K9 acetylation. An in vitro histone acetyltransferase (HAT) assay showed that anserine directly suppressed p300-HAT activity with an IC50 of 1.87 mM. Subsequently, 8-week-old male C57BL/6J mice were subjected to transverse aortic constriction (TAC) and were randomly assigned to receive daily oral treatment with anserine-containing material, Marine Active® (60 or 200 mg/kg anserine) or vehicle for 8 weeks. Echocardiography revealed that anserine 200 mg/kg significantly prevented the TAC-induced increase in left ventricular posterior wall thickness and the decrease in left ventricular fractional shortening. Moreover, anserine significantly suppressed the TAC-induced acetylation of histone H3K9. These results indicate that anserine suppresses TAC-induced systolic dysfunction, at least in part, by inhibiting p300-HAT activity. Anserine may be used as a pharmacological agent for human heart failure therapy. [ABSTRACT FROM AUTHOR]

Cardiac fibrosis is a key aspect of heart failure, leading to reduced ventricular compliance and impaired electrical conduction in the myocardium. Various pathophysiologic conditions can lead to fibrosis in the left ventricle (LV) and/or right ventricle (RV). Despite growing evidence to support the transcriptomic heterogeneity of cardiac fibroblasts (CFs) in healthy and diseased states, there have been no direct comparisons of CFs in the LV and RV. Given the distinct natures of the ventricles, we hypothesized that LV- and RV-derived CFs would display baseline transcriptomic differences that influence their proliferation and differentiation following injury. Bulk RNA sequencing of CFs isolated from healthy murine left and right ventricles indicated that LV-derived CFs may be further along the myofibroblast transdifferentiation trajectory than cells isolated from the RV. Single-cell RNA-sequencing analysis of the two populations confirmed that Postn+ CFs were more enriched in the LV, whereas Igfbp3+ CFs were enriched in the RV at baseline. Notably, following pressure overload injury, the LV developed a larger subpopulation of pro-fibrotic Thbs4+/Cthrc1+ injury-induced CFs, while the RV showed a unique expansion of two less-well-characterized CF subpopulations (Igfbp3+ and Inmt+). These findings demonstrate that LV- and RV-derived CFs display baseline subpopulation differences that may dictate their diverging responses to pressure overload injury. Further study of these subpopulations will elucidate their role in the development of fibrosis and inform on whether LV and RV fibrosis require distinct treatments. [ABSTRACT FROM AUTHOR]

Approximately 50% of Americans have hypertension, which significantly increases the risk of heart failure. In response to increased peripheral resistance in hypertension, intensified mechanical stretch in the myocardium induces cardiomyocyte hypertrophy and fibroblast activation to withstand increased pressure overload. This changes the structure and function of the heart, leading to pathological cardiac remodeling and eventual progression to heart failure. In the presence of hypertensive stimuli, cardiac fibroblasts activate and differentiate to myofibroblast phenotype capable of enhanced extracellular matrix secretion in coordination with other cell types, mainly cardiomyocytes. Both systemic and local renin-angiotensin-aldosterone system activation lead to increased angiotensin II stimulation of fibroblasts. Angiotensin II directly activates fibrotic signaling such as transforming growth factor b/SMAD and mitogen-activated protein kinase (MAPK) signaling to produce extracellular matrix comprised of collagens and matricellular proteins. With the advent of single-cell RNA sequencing techniques, heterogeneity in fibroblast populations has been identified in the left ventricle in models of hypertension and pressure overload. The various clusters of fibroblasts reveal a range of phenotypes and activation states. Select antihypertensive therapies have been shown to be effective in limiting fibrosis, with some having direct actions on cardiac fibroblasts. The present review focuses on the fibroblast-specific changes that occur in response to hypertension and pressure overload, the knowledge gained from single-cell analyses, and the effect of antihypertensive therapies. Understanding the dynamics of hypertensive fibroblast populations and their similarities and differences by sex is crucial for the advent of new targets and personalized medicine. [ABSTRACT FROM AUTHOR]

AbstractContext Andrographolide (Andr) is a bioactive Andr diterpenoid extracted from herbaceous Andrographis paniculata (Burm. F.) Wall. ex Nees (Acanthaceae). Andr can relieve cardiac dysfunction in mice by inhibiting the mitogen-activated protein kinases (MAPK) pathway.Objective This study investigates the efficacy and underlying mechanism of Andr on cardiac hypertrophy in mice.Materials and methods Male C57 mice (20–25 g, 6–8 weeks) were divided into four groups (n = 10 mice/group) as sham group (sham operation), transverse aortic constriction (TAC) model group, TAC + Andr 100 mg/kg group and TAC + Andr 200 mg/kg group. Andr groups were given intragastric administration of Andr (100 and 200 mg/kg) once a day for 14 consecutive days. An in vitro hypertrophy model was established by adding 1 μM of Ang II to H9c2 cells for 48 h induction.Results In TAC-mice, Andr improved echocardiographic indices [reduced LVESD (30.4% or 37.1%) and LVEDD (24.8% or 26.4%), increased EF (22.9% or 42.6%) and FS (25.4% or 52.2%)], reduced BNP (11.5% or 23.6%) and Ang II levels (10.3% or 32.8%), attenuates cardiac fibrosis and reduces cardiac cell apoptosis in TAC mice. In vitro, Andr attenuated cardiomyocyte hypertrophy and decreased the protein expression of GRP78 (67.8%), GRP94 (47.6%), p-PERK (44.9%) and CHOP (66.8%) in Ang-II-induced H9c2 cells and reversed after endoplasmic reticulum (ER) stress agonist Tunicamycin (TN) treatment.Discussion and conclusions Andr was found to be an anti-hypertrophic regulator, which could attenuate cardiac hypertrophy by suppressing ER stress. It may be a new therapeutic drug for cardiac hypertrophy.

Background/Aim: The impact of myocardial stressors such as high-fat diet (HFD) and pressure overload has been extensively studied. Toll-like receptor 4 (TLR4) deficiency has been suggested to have a protective role in response to these stressors, although some conflicting data exist. Furthermore, there is limited information about the role of TLR4 on cardiac remodeling in response to long-term exposure to stressors. This study aims to investigate the effects of TLR4 deficiency on cardiac histology and physiology in response to chronic stressors. Methods: TLR4-deficient (TLR4−/−) and wild-type (WT) mice were subjected to either HFD or a normal diet (ND) for 28 weeks. Another group underwent abdominal aortic constriction (AAC) or a sham procedure and was monitored for 12 weeks. Inflammatory markers, histology, and echocardiography were used to assess the effects of these interventions. Results: TLR4−/− mice exhibited reduced cardiac hypertrophy and fibrosis after long-term HFD exposure compared to ND without affecting cardiac function. On the other hand, TLR4 deficiency worsened cardiac function in response to AAC, leading to decreased ejection fraction (EF%) and increased end-systolic volume (ESV). Conclusions: TLR4 deficiency provided protection against HFD-induced myocardial inflammation but impaired hemodynamic cardiac function under pressure overload conditions. These findings highlight the crucial role of TLR4 and its downstream signaling pathway in maintaining cardiac output during physiologic cardiac hypertrophy in response to pressure overload. [ABSTRACT FROM AUTHOR]

Background: Gasdermin D (GSDMD) forms membrane pores to execute pyroptosis. But the mechanism of how cardiomyocyte pyroptosis induces cardiac remodeling in pressure overload remains unclear. We investigated the role of GSDMD-mediated pyroptosis in the pathogenesis of cardiac remodeling in pressure overload. Methods: Wild-type (WT) and cardiomyocyte-specific GSDMD-deficient (GSDMD-CKO) mice were subjected to transverse aortic constriction (TAC) to induce pressure overload. Four weeks after surgery, left ventricular structure and function were evaluated by echocardiographic, invasive hemodynamic and histological analysis. Pertinent signaling pathways related to pyroptosis, hypertrophy and fibrosis were investigated by histochemistry, RT-PCR and western blotting. The serum levels of GSDMD and IL-18 collected from healthy volunteers or hypertensive patients were measured by ELISA. Results: We found TAC induced cardiomyocyte pyroptosis and release of pro-inflammatory cytokines IL-18. The serum GSDMD level was significantly higher in hypertensive patients than in healthy volunteers, and induced more dramatic release of mature IL-18. GSDMD deletion remarkably mitigated TAC-induced cardiomyocyte pyroptosis. Furthermore, GSDMD deficiency in cardiomyocytes significantly reduced myocardial hypertrophy and fibrosis. The deterioration of cardiac remodeling by GSDMD-mediated pyroptosis was associated with activating JNK and p38 signaling pathways, but not ERK or Akt signaling pathway. Conclusion: In conclusion, our results demonstrate that GSDMD serves as a key executioner of pyroptosis in cardiac remodeling induced by pressure overload. GSDMD-mediated pyroptosis activates JNK and p38 signaling pathways, and this may provide a new therapeutic target for cardiac remodeling induced by pressure overload. [ABSTRACT FROM AUTHOR]

Andrographolide (Andr) is a bioactive Andr diterpenoid extracted from herbaceous Andrographis paniculata (Burm. F.) Wall. ex Nees (Acanthaceae). Andr can relieve cardiac dysfunction in mice by inhibiting the mitogen-activated protein kinases (MAPK) pathway. This study investigates the efficacy and underlying mechanism of Andr on cardiac hypertrophy in mice. Male C57 mice (20–25 g, 6–8 weeks) were divided into four groups (n = 10 mice/group) as sham group (sham operation), transverse aortic constriction (TAC) model group, TAC + Andr 100 mg/kg group and TAC + Andr 200 mg/kg group. Andr groups were given intragastric administration of Andr (100 and 200 mg/kg) once a day for 14 consecutive days. An in vitro hypertrophy model was established by adding 1 μM of Ang II to H9c2 cells for 48 h induction. In TAC-mice, Andr improved echocardiographic indices [reduced LVESD (30.4% or 37.1%) and LVEDD (24.8% or 26.4%), increased EF (22.9% or 42.6%) and FS (25.4% or 52.2%)], reduced BNP (11.5% or 23.6%) and Ang II levels (10.3% or 32.8%), attenuates cardiac fibrosis and reduces cardiac cell apoptosis in TAC mice. In vitro, Andr attenuated cardiomyocyte hypertrophy and decreased the protein expression of GRP78 (67.8%), GRP94 (47.6%), p-PERK (44.9%) and CHOP (66.8%) in Ang-II-induced H9c2 cells and reversed after endoplasmic reticulum (ER) stress agonist Tunicamycin (TN) treatment. Andr was found to be an anti-hypertrophic regulator, which could attenuate cardiac hypertrophy by suppressing ER stress. It may be a new therapeutic drug for cardiac hypertrophy. [ABSTRACT FROM AUTHOR]

We employed an early training exercise program, immediately after recovery from surgery, and before severe cardiac hypertrophy, to study the underlying mechanism involved with the amelioration of cardiac dysfunction in aortic stenosis (AS) rats. As ET induces angiogenesis and oxygen support, we aimed to verify the effect of exercise on myocardial lipid metabolism disturbance. Wistar rats were divided into Sham, trained Sham (ShamT), AS and trained AS (AST). The exercise consisted of 5‐week sessions of treadmill running for 16 weeks. Statistical analysis was conducted by anova or Kruskal–Wallis test and Goodman test. A global correlation between variables was also performed using a two‐tailed Pearson's correlation test. AST rats displayed a higher functional capacity and a lower cardiac remodelling and dysfunction when compared to AS, as well as the myocardial capillary rarefaction was prevented. Regarding metabolic properties, immunoblotting and enzymatic assay raised beneficial effects of exercise on fatty acid transport and oxidation pathways. The correlation assessment indicated a positive correlation between variables of angiogenesis and FA utilisation, as well as between metabolism and echocardiographic parameters. In conclusion, early exercise improves exercise tolerance and attenuates cardiac structural and functional remodelling. In parallel, exercise attenuated myocardial capillary and lipid metabolism derangement in rats with aortic stenosis‐induced heart failure. [ABSTRACT FROM AUTHOR]

Sacubitril/valsartan (Sac/Val) belongs to the group of angiotensin receptor–neprilysin inhibitors and has been used for the treatment of heart failure (HF) for several years. The mechanisms that mediate the beneficial effects of Sac/Val are not yet fully understood. In this study we investigated whether Sac/Val influences the two proteolytic systems, the ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway (ALP), in a mouse model of pressure overload induced by transverse aortic constriction (TAC) and in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) treated with endothelin-1 (ET1) serving as a human cellular model of hypertrophy. TAC mice showed a continuous decline in cardiac function starting from day 14 after surgery. Administration of Sac/Val for 6 weeks counteracted the deterioration of cardiac function and attenuated hypertrophy and fibrosis in TAC mice. The expression of ALP key markers did not differ between the groups. Proteasome activity was higher in TAC mice and normalized by Sac/Val. In hiPSC-CMs, all treatments (Sac, Val or Sac/Val) normalized mean cell area. However, Sac alone or in combination with Val, but not Val alone prevented ET1-induced hypertrophic gene program and proteomic changes. In conclusion, Sac/Val normalized proteasome activity, improved cardiac function and reduced fibrosis and hypertrophy in TAC mice. Molecular analysis in hiPSC-CMs suggests that a major part of the beneficial effects of Sac/Val is derived from the Sac action rather than from Val.

Background Alveolar hypoxia is protective in the context of cardiovascular and ischemic heart disease; however, the underlying mechanisms are incompletely understood. The present study sought to test the hypothesis that hypoxia is cardioprotective in left ventricular pressure overload (LVPO)–induced heart failure. We furthermore aimed to test that overlapping mechanisms promote cardiac recovery in heart failure patients following left ventricular assist device‐mediated mechanical unloading and circulatory support. Methods and Results We established a novel murine model of combined chronic alveolar hypoxia and LVPO following transverse aortic constriction (HxTAC). The HxTAC model is resistant to cardiac hypertrophy and the development of heart failure. The cardioprotective mechanisms identified in our HxTAC model include increased activation of HIF (hypoxia‐inducible factor)‐1α–mediated angiogenesis, attenuated induction of genes associated with pathological remodeling, and preserved metabolic gene expression as identified by RNA sequencing. Furthermore, LVPO decreased Tbx5 and increased Hsd11b1 mRNA expression under normoxic conditions, which was attenuated under hypoxic conditions and may induce additional hypoxia‐mediated cardioprotective effects. Analysis of samples from patients with advanced heart failure that demonstrated left ventricular assist device–mediated myocardial recovery revealed a similar expression pattern for TBX5 and HSD11B1 as observed in HxTAC hearts. Conclusions Hypoxia attenuates LVPO‐induced heart failure. Cardioprotective pathways identified in the HxTAC model might also contribute to cardiac recovery following left ventricular assist device support. These data highlight the potential of our novel HxTAC model to identify hypoxia‐mediated cardioprotective mechanisms and therapeutic targets that attenuate LVPO‐induced heart failure and mediate cardiac recovery following mechanical circulatory support.

Systemic and pulmonary arterial hypertension (PAH) can induce left and right ventricular hypertrophy, respectively, but common therapeutic targets for both left and right hypertrophy are limited. In this study, we attempt to explore potential common therapeutic targets and screen out potential target drugs for further study. Cardiac mRNA expression profiles in mice with transverse aortic constriction (TAC) and pulmonary arterial constriction (PAC) are obtained from online databases. After bioinformatics analyses, we generate TAC and PAC mouse models to validate the phenotypes of cardiac remodelling as well as the identified hub genes. Bioinformatics analyses show that there are 214 independent differentially expressed genes (DEGs) in GSE136308 (TAC related) and 2607 independent DEGs in GSE30922 (PAC related), while 547 shared DEGs are associated with the function of the extracellular matrix (ECM) or involved in the PI3K-Akt signaling pathway, cytokine-cytokine receptor interactions, and ECM-receptor interactions. We identifyd Fn1, Il6, Col1a1, Igf1, Col1a2, Timp1, Col3a1, Cd44, Ctgf and Postn as hub genes of the shared DEGs, and most of them are associated with myocardial fibrosis. Those hub genes and phenotypes of cardiac remodelling are validated in our TAC and PAC mouse models. Furthermore, we identify dehydroisoandrosterone (DHEA), iloprost and 4,5-dianilinophthalimide (DAPH) as potential therapeutic drugs targeting both left and right ventricular hypertrophy and validate the effect of DHEA. These findings suggest that DHEA could be an effective drug for pressure overload-induced left or right ventricular hypertrophy by regulating the shared hub differentially expressed genes associated with fibrosis.

Cardiac fibrosis is a central pathological feature in several cardiac diseases, but the underlying molecular players are insufficiently understood. The extracellular matrix proteoglycan versican is elevated in heart failure and suggested to be a target for treatment. However, the temporal expression and spatial distribution of versican and the versican cleavage fragment containing the neoepitope DPEAAE in cardiac fibrosis remains to be elucidated. In this study, we have examined versican during cardiac fibrosis development in a murine pressure overload model and in patients with cardiomyopathies. We found that versican, mainly the V1 isoform, was expressed immediately after induction of pressure overload, preceding collagen accumulation, and versican protein levels extended from the perivascular region into the cardiac interstitium. In addition, we found increased production of versican by collagen expressing fibroblasts, and that it was deposited extensively in the fibrotic extracellular matrix during pressure overload. In cardiac cell cultures, the expression of versican was induced by the pro-fibrotic transforming growth factor beta and mechanical stretch. Furthermore, we observed that the proteolytic cleavage of versican (DPEAAE fragment) increased in the late phase of fibrosis development during pressure overload. In patients with hypertrophic and dilated cardiomyopathies, we found elevated levels of versican and a positive correlation between versican and collagen mRNA in the heart, as well as increased cleavage of full-length protein. Taken together, the temporal expression profile and the spatial distribution of both the full-length versican and the DPEAAE fragment observed in this study indicates a role for versican in development of cardiac fibrosis.

Aims: Endothelial dysfunction plays a pivotal role in atherosclerosis, but the detailed mechanism remains incomplete understood. Nogo-B is an endoplasmic reticulum (ER)-localized protein mediating ER-mitochondrial morphology. We previously showed endothelial Nogo-B as a key regulator of endothelial function in the setting of hypertension. Here, we aim to further assess the role of Nogo-B in coronary atherosclerosis in ApoE−/− mice with pressure overload. Methods and results: We generated double knockout (DKO) mouse models of systemically or endothelium-specifically excising Nogo-A/B gene on an ApoE−/− background. After 7 weeks of transverse aortic constriction (TAC) surgery, compared to ApoE−/− mice DKO mice were resistant to the development of coronary atherosclerotic lesions and plaque rapture. Sustained elevation of Nogo-B and adhesion molecules (VCAM-1/ICAM-1), early markers of atherosclerosis, was identified in heart tissues and endothelial cells (ECs) isolated from TAC ApoE−/− mice, changes that were significantly repressed by Nogo-B deficiency. In cultured human umbilical vein endothelial cells (HUVECs) exposure to inflammatory cytokines (TNF-α, IL-1β), Nogo-B was upregulated and activated reactive oxide species (ROS)-p38-p65 signaling axis. Mitofusin 2 (Mfn2) is a key protein tethering ER to mitochondria in ECs, and we showed that Nogo-B expression positively correlated with Mfn2 protein level. And Nogo-B deletion in ECs or in ApoE−/− mice reduced Mfn2 protein content and increased ER-mitochondria distance, reduced ER-mitochondrial Ca2+ transport and mitochondrial ROS generation, and prevented VCAM-1/ICAM-1 upregulation and EC dysfunction, eventually restrained atherosclerotic lesions development. Conclusion: Our study revealed that Nogo-B is a critical modulator in promoting endothelial dysfunction and consequent pathogenesis of coronary atherosclerosis in pressure overloaded hearts of ApoE−/− mice. Nogo-B may hold the promise to be a common therapeutic target in the setting of hypertension.

Background: Inflammation contributes to heart failure (HF) development, the progression from left ventricular failure to pulmonary remodeling, and the consequent right ventricular hypertrophy and failure. NK1.1 plays a critical role in Natural killer (NK) and NK T (NKT) cells, but the role of NK1.1 in HF development and progression is unknown. Methods: We studied the effects of NK1.1 inhibition on transverse aortic constriction (TAC)-induced cardiopulmonary inflammation, HF development, and HF progression in immunocompetent male mice of C57BL/6J background. Results: We found that NK1.1+ cell-derived interferon gamma+ (IFN-g +) was significantly increased in pulmonary tissues after HF. In addition, anti-NK1.1 antibodies simultaneously abolished both NK1.1+ cells, including the NK1.1+NK and NK1.1+NKT cells in peripheral blood, spleen, and lung tissues, but had no effect on cardiopulmonary structure and function under control conditions. However, systemic inhibition of NK1.1 signaling by anti-NK1.1 antibodies significantly rescued mice from TAC-induced left ventricular inflammation, fibrosis, and failure. Inhibition of NK1.1 signaling also significantly attenuated TAC-induced pulmonary leukocyte infiltration, fibrosis, vessel remodeling, and consequent right ventricular hypertrophy. Moreover, inhibition of NK1.1 signaling significantly reduced TAC-induced pulmonary macrophage and dendritic cell infiltration and activation. Conclusions: Our data suggest that inhibition of NK1.1 signaling is effective in attenuating systolic overload-induced cardiac fibrosis, dysfunction, and consequent pulmonary remodeling in immunocompetent mice through modulating the cardiopulmonary inflammatory response. [ABSTRACT FROM AUTHOR]

Inflammation is an integral component of cardiovascular disease and is thought to contribute to cardiac dysfunction and heart failure. While ischemia-induced inflammation has been extensively studied in the heart, relatively less is known regarding cardiac inflammation during non-ischemic stress. Recent work has implicated a role for Yes-associated protein (YAP) in modulating inflammation in response to ischemic injury; however, whether YAP influences inflammation in the heart during non-ischemic stress is not described. We hypothesized that YAP mediates a pro-inflammatory response during pressure overload (PO)-induced non-ischemic injury, and that targeted YAP inhibition in the myeloid compartment is cardioprotective. In mice, PO elicited myeloid YAP activation, and myeloid-specific YAP knockout mice (YAPF/F;LysMCre) subjected to PO stress had better systolic function, and attenuated pathological remodeling compared to control mice. Inflammatory indicators were also significantly attenuated, while pro-resolving genes including Vegfa were enhanced, in the myocardium, and in isolated macrophages, of myeloid YAP KO mice after PO. Experiments using bone marrow-derived macrophages (BMDMs) from YAP KO and control mice demonstrated that YAP suppression shifted polarization toward a resolving phenotype. We also observed attenuated NLRP3 inflammasome priming and function in YAP deficient BMDMs, as well as in myeloid YAP KO hearts following PO, indicating disruption of inflammasome induction. Finally, we leveraged nanoparticle-mediated delivery of the YAP inhibitor verteporfin and observed attenuated PO-induced pathological remodeling compared to DMSO nanoparticle control treatment. These data implicate myeloid YAP as an important molecular nodal point that facilitates cardiac inflammation and fibrosis during PO stress and suggest that selective inhibition of YAP may prove a novel therapeutic target in non-ischemic heart disease. [Display omitted] • YAP deficient macrophages have reduced pro-inflammatory and chemotactic gene expression. • YAP deficient macrophages have enhanced resolving and angiogenic gene expression. • Inhibition of myeloid YAP protects against pathological cardiac remodeling and dysfunction. [ABSTRACT FROM AUTHOR]

Pathological cardiac hypertrophy is a key risk factor for the development of heart failure and predisposes individuals to cardiac arrhythmia and sudden death. While physiological cardiac hypertrophy is adaptive, hypertrophy resulting from conditions comprising hypertension, aortic stenosis, or genetic mutations, such as hypertrophic cardiomyopathy, is maladaptive. Here, we highlight the essential role and reciprocal interactions involving both cardiomyocytes and non-myocardial cells in response to pathological conditions. Prolonged cardiovascular stress causes cardiomyocytes and non-myocardial cells to enter an activated state releasing numerous pro-hypertrophic, pro-fibrotic, and pro-inflammatory mediators such as vasoactive hormones, growth factors, and cytokines, i.e., commencing signaling events that collectively cause cardiac hypertrophy. Fibrotic remodeling is mediated by cardiac fibroblasts as the central players, but also endothelial cells and resident and infiltrating immune cells enhance these processes. Many of these hypertrophic mediators are now being integrated into computational models that provide system-level insights and will help to translate our knowledge into new pharmacological targets. This perspective article summarizes the last decades' advances in cardiac hypertrophy research and discusses the herein-involved complex myocardial microenvironment and signaling components. [ABSTRACT FROM AUTHOR]

Hemodynamics is the eternal theme of the circulatory system. Abnormal hemodynamics and cardiac and pulmonary development intertwine to form the most important features of children with congenital heart diseases (CHDs), thus determining these children’s long-term quality of life. Here, we review the varieties of hemodynamic abnormalities that exist in children with CHDs, the recently developed neonatal rodent models of CHDs, and the inspirations these models have brought us in the areas of cardiomyocyte proliferation and maturation, as well as in alveolar development. Furthermore, current limitations, future directions, and clinical decision making based on these inspirations are highlighted. Understanding how CHD-associated hemodynamic scenarios shape postnatal heart and lung development may provide a novel path to improving the long-term quality of life of children with CHDs, transplantation of stem cell-derived cardiomyocytes, and cardiac regeneration.

Cardiac fibrosis is a key aspect of heart failure, leading to reduced ventricular compliance and impaired electrical conduction in the myocardium. Various pathophysiologic conditions can lead to fibrosis in the left ventricle (LV) and/or right ventricle (RV). Despite growing evidence to support the transcriptomic heterogeneity of cardiac fibroblasts (CFs) in healthy and diseased states, there have been no direct comparisons of CFs in the LV and RV. Given the distinct natures of the ventricles, we hypothesized that LV- and RV-derived CFs would display baseline transcriptomic differences that influence their proliferation and differentiation following injury. Bulk RNA sequencing of CFs isolated from healthy murine left and right ventricles indicated that LV-derived CFs may be further along the myofibroblast transdifferentiation trajectory than cells isolated from the RV. Single-cell RNA-sequencing analysis of the two populations confirmed that Postn+ CFs were more enriched in the LV, whereas Igfbp3+ CFs were enriched in the RV at baseline. Notably, following pressure overload injury, the LV developed a larger subpopulation of pro-fibrotic Thbs4+/Cthrc1+ injury-induced CFs, while the RV showed a unique expansion of two less-well-characterized CF subpopulations (Igfbp3+ and Inmt+). These findings demonstrate that LV- and RV-derived CFs display baseline subpopulation differences that may dictate their diverging responses to pressure overload injury. Further study of these subpopulations will elucidate their role in the development of fibrosis and inform on whether LV and RV fibrosis require distinct treatments.

Anserine, an imidazole dipeptide, is present in the muscles of birds and fish and has various bioactivities, such as anti-inflammatory and anti-fatigue effects. However, the effect of anserine on the development of heart failure remains unknown. We cultured primary cardiomyocytes with 0.03 mM to 10 mM anserine and stimulated them with phenylephrine for 48 h. Anserine significantly suppressed the phenylephrine-induced increases in cardiomyocyte hypertrophy, ANF and BNP mRNA levels, and histone H3K9 acetylation. An in vitro histone acetyltransferase (HAT) assay showed that anserine directly suppressed p300-HAT activity with an IC50 of 1.87 mM. Subsequently, 8-week-old male C57BL/6J mice were subjected to transverse aortic constriction (TAC) and were randomly assigned to receive daily oral treatment with anserine-containing material, Marine Active® (60 or 200 mg/kg anserine) or vehicle for 8 weeks. Echocardiography revealed that anserine 200 mg/kg significantly prevented the TAC-induced increase in left ventricular posterior wall thickness and the decrease in left ventricular fractional shortening. Moreover, anserine significantly suppressed the TAC-induced acetylation of histone H3K9. These results indicate that anserine suppresses TAC-induced systolic dysfunction, at least in part, by inhibiting p300-HAT activity. Anserine may be used as a pharmacological agent for human heart failure therapy.

The lipid metabolizing enzyme 12/15 lipoxygenase (12/15LOX) induces proinflammatory responses that may increase cardiovascular and renal complications after cardiac insult. To define the role of 12/15LOX, 8–12-week-old male C57BL/6J wild-type (WT; n = 49) and 12/15LOX−/− mice (n = 50) were subject to transverse aortic constriction (TAC) and monitored for 7, 28, and 56 days (d) post-TAC. Compared with WT, 12/15LOX−/− mice experienced less left ventricle (LV) dysfunction with limited LV hypertrophy and lung edema post-TAC. 12/15LOX deletion decreased TAC-induced proinflammatory mediators 12-HETE and prostaglandins with modulation in mir-7a-5p, mir 26a-5p, miR-21e-5p, and miR-107-3p during chronic remodeling period (after d28). At d7 post-TAC, 12/15LOX−/− mice showed increased cardiac gene expression of Arg-1 and the prostanoid receptors EP2 and EP4. The EP4 receptor expression was consistently elevated from d7 till d56 in 12/15LOX−/− mice post-TAC compared with WT controls. Post-TAC, wheat germ agglutinin staining revealed less cardiomyocyte hypertrophy at d28 and d56 in 12/15LOX−/− mice compared with WT. TAC-induced vascular remodeling was marked by disruption in the endothelium, evident by irregular CD31 staining and increased alpha-smooth muscle actin (α-SMA) in WT mice at d28 and d56. Compared to WT, 12/15LOX−/− mice exhibited a diminished expression of NGAL in the kidney, suggesting that 12/15LOX−/− reduced cardiorenal dysfunction post-TAC. In WT-TAC mice, structural analyses of the kidney revealed glomerular swelling during the maladaptive phase of heart failure, with decreases in the capsula glomeruli space and glomerular sclerosis compared to 12/15LOX−/− mice. Overall, vascular and kidney inflammation markers were higher in WT than in 12/15LOX−/− post-TAC. Thus, deletion of 12/15LOX limits LV hypertrophy associated with perivascular inflammation and cardiorenal remodeling after pressure overload. Deficiency of 12/15 LOX serves a dual role in delaying an early adaptive interstitial remodeling with long-term protective effects on cardiac hypertrophy and cardiac fibrosis and detrimental adverse vascular remodeling during later maladaptive remodeling after pressure overload.

TRIM-containing 44 (TRIM44) is a promoter of multiple cancers. However, its role in cardiac hypertrophy has not been elucidated. This study explored the role of TRIM44 on pressure overload-induced cardiac hypertrophy in mice. Mice were subjected to aortic banding to establish an adverse cardiac hypertrophy model, followed by the administration of AAV9-TRIM44 or AAV9shTRIM44 to overexpress or knock down TRIM44. Echocardiography was used to assess cardiac function. H9c2 cells were cultured and transfected with either Ad-TRIM44 or TRIM44 siRNA to overexpress or silence TRIM44. Cells were also stimulated with angiotensin II to establish a cardiomyocyte hypertrophy model. Results indicated that TRIM44 was downregulated in mice hearts and cardiomyocytes that were treated with aortic banding or angiotensin II. TRIM44 overexpression in mice hearts aggravated cardiac hypertrophy and fibrosis, as well as inhibited cardiac function post-aortic banding. Moreover, mice with TRIM44 overexpression displayed increased ferroptosis post-aortic banding. Mice with TRIM44 knockdown revealed ameliorated cardiac hypertrophy, ferroptosis, and fibrosis, as well as improved cardiac function post-aortic banding. In H9c2 cells transfected with Ad-TRIM44, angiotensin II-induced ferroptosis was enhanced, while cells with silenced TRIM44 reported reduced ferroptosis post-angiotensin II administration. Furthermore, TRIM44 interacted with TLR4, which increased the expression of NOX4 and subsequently augmented ferroptosis-associated protein levels. By using TLR4 knockout mice, the inhibitory role of TRIM44 was reduced post-aortic banding. Taken together, TRIM44 aggravated pressure overload-induced cardiac hypertrophy via increased TLR4/NOX4-associated ferroptosis. Key messages: TRIM44 could aggregate pressure overload-induced cardiac hypertrophy via increasing TLR4-NOX4 associated ferroptosis. Target TRIM44 may become a new therapeutic method for preventing or treating pressure overload-induced cardiac hypertrophy. [ABSTRACT FROM AUTHOR]

Purpose of the Review: Tricuspid regurgitation is associated with increased mortality in proportion to right ventricular adaptation to increased volume loading and pulmonary artery pressure. We here review recent progress in the understanding of right ventricular adaptation to pre- and after-loading conditions for improved recommendations of tricuspid valve repair. Recent Findings: Trans-catheter tricuspid valve repair has made the correction of tricuspid regurgitation more easily available, triggering a need of tighter indications. Several studies have shown the feasibility and relevance to the indications of tricuspid valve repair of imaging of right ventricular ejection fraction measured by magnetic resonance imaging or 3D-echocardiography, and the 2D-echocardiography of the tricuspid annular plane systolic excursion to systolic pulmonary artery pressure ratio combined with invasively determined mean pulmonary artery pressure and pulmonary vascular resistance. Summary: Improved definitions of right ventricular failure and pulmonary hypertension may be considered in future recommendations on the treatment of tricuspid regurgitation. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is the end stage of the progression of many cardiovascular diseases. Cardiac remodeling is the main pathophysiological process of cardiac function deterioration in HF patients. Inflammation is a key factor that stimulates cardiomyocyte hypertrophy, fibroblast proliferation, and transformation leading to myocardial remodeling, which severity is significantly related to the prognosis of patients. SAA1 (Serum amyloid A1) is a lipid‐binding protein that was an important regulator involved in inflammation, whose biological functions in the heart remain rarely known. In this research, we intended to test the role of SAA1 in SAA1‐deficient (SAA1−/−), and wild‐type mice were exposed to transverse aortic banding surgery to establish the model of cardiac remodeling. Besides, we assessed the functional effects of SAA1 on cardiac hypertrophy and fibrosis. The expression of SAA1 was increased in the mice transverse aortic banding model induced by pressure overload. After 8 weeks of transverse aortic banding, SAA1−/− mice displayed a lower level of cardiac fibrosis than wild‐type mice, but did not significantly influence the cardiomyocyte hypertrophy. In addition, there was also no significant difference in cardiac fibrosis severity between wild‐type‐sham and knockout‐sham mice. These findings are the first to reveal SAA1 absence hinders cardiac fibrosis after 8 weeks of transverse aortic banding. Furthermore, SAA1 deficiency had no significant effect on cardiac fibrosis and hypertrophy in the sham group in this study. [ABSTRACT FROM AUTHOR]

Aortic stiffness is an independent risk factor for aortic diseases such as aortic dissection which commonly occurred with aging and hypertension. Chemokine receptor CXCR6 is critically involved in vascular inflammation and remodeling. Here, we investigated whether and how CXCR6 plays a role in aortic stiffness caused by pressure overload. CXCR6−/− and WT mice underwent transverse aortic constriction (TAC) surgery for 8 weeks. CXCR6 deficiency significantly improved TAC-induced aortic remodeling and endothelial dysfunction by decreasing CD11c+ macrophage infiltration, suppressing VCAM-1 and ICAM-1, reducing collagen deposition, and downregulating MMP12 and osteopontin in the aorta. Consistently, blocking the CXCL16/CXCR6 axis also reduced aortic accumulation of CD11c+ macrophages and vascular stiffness but without affecting the release of TNF-α and IL-6 from the aorta. Furthermore, pressure overload inhibited aortic release of exosomes, which could be reversed by suppressing CXCR6 or CXCL16. Inhibition of exosome release by GW4869 significantly aggravated TAC-induced aortic calcification and stiffness. By exosomal microRNA microarray analysis, we found that microRNA-29b was significantly reduced in aortic endothelial cells (AECs) receiving TAC. Intriguingly, blocking the CXCL16/CXCR6 axis restored the expression of miR-29b in AECs. Finally, overexpression of miR-29b significantly increased eNOS and reduced MMPs and collagen in AECs. By contrast, antagonizing miR-29b in vivo further enhanced TAC-induced expressions of MMP12 and osteopontin, aggravated aortic fibrosis, calcification, and stiffness. Our study demonstrated a key role of the CXCL16/CXCR6 axis in macrophage recruitment and macrophage-mediated aortic stiffness under pressure overload through an exosome-miRNAs-dependent manner. [ABSTRACT FROM AUTHOR]

These data suggest that Perm1 protects the heart against pressure overload by restoring oxidative metabolism, and these beneficial effects of Perm1 are mediated through Mic60. Perm1 Protects the Heart From Pressure Overload-Induced Dysfunction by Promoting Oxidative Metabolism Keywords: MICOS; mitochondria; oxidative metabolism; Perm1; pressure overload EN MICOS mitochondria oxidative metabolism Perm1 pressure overload 916 919 4 03/14/23 20230314 NES 230314 Defects in ATP production lead to cardiac dysfunction and heart failure, whereas maintaining appropriate energy production preserves normal heart function and restoring reduced mitochondrial function mitigates heart failure in human and animal models. [Extracted from the article]

Fetal heart failure (FHF) is a condition of inability of the fetal heart to deliver adequate blood flow for tissue perfusion in various organs, especially the brain, heart, liver and kidneys. FHF is associated with inadequate cardiac output, which is commonly encountered as the final outcome of several disorders and may lead to intrauterine fetal death or severe morbidity. Fetal echocardiography plays an important role in diagnosis of FHF as well as of the underlying causes. The main findings supporting the diagnosis of FHF include various signs of cardiac dysfunction, such as cardiomegaly, poor contractility, low cardiac output, increased central venous pressures, hydropic signs, and the findings of specific underlying disorders. This review will present a summary of the pathophysiology of fetal cardiac failure and practical points in fetal echocardiography for diagnosis of FHF, focusing on essential diagnostic techniques used in daily practice for evaluation of fetal cardiac function, such as myocardial performance index, arterial and systemic venous Doppler waveforms, shortening fraction, and cardiovascular profile score (CVPs), a combination of five echocardiographic markers indicative of fetal cardiovascular health. The common causes of FHF are reviewed and updated in detail, including fetal dysrhythmia, fetal anemia (e.g., alpha-thalassemia, parvovirus B19 infection, and twin anemia-polycythemia sequence), non-anemic volume load (e.g., twin-to-twin transfusion, arteriovenous malformations, and sacrococcygeal teratoma, etc.), increased afterload (intrauterine growth restriction and outflow tract obstruction, such as critical aortic stenosis), intrinsic myocardial disease (cardiomyopathies), congenital heart defects (Ebstein anomaly, hypoplastic heart, pulmonary stenosis with intact interventricular septum, etc.) and external cardiac compression. Understanding the pathophysiology and clinical courses of various etiologies of FHF can help physicians make prenatal diagnoses and serve as a guide for counseling, surveillance and management. [ABSTRACT FROM AUTHOR]

Pressure overload hypertrophy of the left ventricle is a common result of many cardiovascular diseases. Androgens show anabolic effects in skeletal muscles, but also in myocardial hypertrophy. We carefully reviewed literature regarding possible effects of androgens on specific left ventricular hypertrophy in pressure overload conditions excluding volume overload conditions or generel sex differences. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to evaluate whether [68 Ga]Ga-FAPI-04 PET/CT could characterize the early stages of cardiac fibrosis in pressure overload heart failure. Methods: Sprague–Dawley rats underwent abdominal aortic constriction (AAC) (n = 12) and sham surgery (n = 10). All rats were scanned with [68 Ga]Ga-FAPI-04 PET/CT at 2, 4, and 8 weeks after surgery. The expression of fibroblast activation protein (FAP) in the myocardium was detected by immunohistochemistry. [68 Ga]Ga-FAPI-04 PET signal and FAP expression were compared between two groups. Results: Compared with the sham group, the AAC group presented with decreased ejection fraction (EF) and fractional shortening (FS) and increased left ventricular internal dimensions in diastole (LVIDd) and systole (LVIDs) at 4 and 8 weeks (all p < 0.01). The AAC group showed higher [68 Ga]Ga-FAPI-04 accumulation in the heart than the sham group at 2, 4, and 8 weeks, and FAPI increased significantly from 2 to 8 weeks (all p < 0.001). Immunohistochemistry confirmed the higher density of the FAP+ area in the AAC group. The intensity of the [68 Ga]Ga-FAPI-04 correlated with the density of the FAP+ area (p < 0.001). The expression of the [68 Ga]Ga-FAPI-04 at 4 weeks correlated with the deterioration of cardiac function at 8 weeks (EF: R = − 0.87; FS: R = − 0.72; LVIDd: R = 0.77; LVIDs: R = 0.79; all p < 0.001). The AAC group also showed an increased [68 Ga]Ga-FAPI-04 signal in the liver, peaking at 4 weeks and then declining. Cardiac and liver PET signals correlated at 4 weeks in the AAC group (R = 0.69, p = 0.0010), suggesting an early fibrotic link between organs. A combination of the [68 Ga]Ga-FAPI-04 intensity in the heart and liver at 4 weeks better predicted the deterioration of cardiac function at 8 weeks. Conclusions: The activated fibroblasts in the heart and liver after pressure overload can be monitored by [68 Ga]Ga-FAPI-04 PET/CT, which reveals an early fibrotic link in cardio-liver interactions and could better predict nonischemic heart failure prognosis. [ABSTRACT FROM AUTHOR]

The incidence of heart failure mainly resulting from cardiac hypertrophy and fibrosis increases sharply in post-menopausal women compared with men at the same age, which indicates a cardioprotective role of estrogen. Previous studies in our group have shown that the novel estrogen receptor G Protein Coupled Receptor 30 (GPR30) could attenuate myocardial fibrosis caused by ischemic heart disease. However, the role of GPR30 in myocardial hypertrophy in ovariectomized mice has not been investigated yet. In this study, female mice with bilateral ovariectomy or sham surgery underwent transverse aortic constriction (TAC) surgery. After 8 weeks, mice in the OVX + TAC group exhibited more severe myocardial hypertrophy and fibrosis than mice in the TAC group. G1, the specific agonist of GPR30, could attenuate myocardial hypertrophy and fibrosis of mice in the OVX + TAC group. Furthermore, the expression of LC3II was significantly higher in the OVX + TAC group than in the OVX + TAC + G1 group, which indicates that autophagy might play an important role in this process. An in vitro study showed that G1 alleviated AngiotensionII (AngII)-induced hypertrophy and reduced the autophagy level of H9c2 cells, as revealed by LC3II expression and tandem mRFP-GFP-LC3 fluorescence analysis. Additionally, Western blot results showed that the AKT/mTOR pathway was inhibited in the AngII group, whereas it was restored in the AngII + G1 group. To further verify the mechanism, PI3K inhibitor LY294002 or autophagy activator rapamycin was added in the AngII + G1 group, and the antihypertrophy effect of G1 on H9c2 cells was blocked by LY294002 or rapamycin. In summary, our results demonstrate that G1 can attenuate cardiac hypertrophy and fibrosis and improve the cardiac function of mice in the OVX + TAC group through AKT/mTOR mediated inhibition of autophagy. Thus, this study demonstrates a potential option for the drug treatment of pressure overload-induced cardiac hypertrophy in postmenopausal women. [ABSTRACT FROM AUTHOR]

Background: Myocardial hypertrophy and dilation are key features of cardiomyopathies and involve several cellular and molecular events. A disintegrin and metalloproteinases (ADAMs) are membrane-bound proteinases with diverse functions whose role in heart disease remains underexplored. ADAM15 is expressed in the heart and is downregulated in the failing human heart. We investigated the role ADAM15 in pressure overload cardiomyopathy.Methods: We assessed ADAM15 levels in myocardial specimens from patients. Its direct role in pressure overload was investigated by subjecting wildtype and Adam15-deficient mice to transverse aortic constriction (TAC).Results: ADAM15 levels did not change in patients with concentric hypertrophy, but markedly decreased in eccentric hypertrophy and heart failure. Loss of ADAM15 alone did not cause cardiomyopathy in mice (1 year old). After TAC, Adam15-/- mice exhibited worsened eccentric hypertrophy and dilation with greater increase in hypertrophy markers (pJNK, pERK1/2; Nppb, Nppa, Myh7, Acta1) compared with wildtype-TAC. Expression of integrin-α7 (but not integrin β1) increased significantly more in Adam15-/--TAC hearts, while the interaction of these integrins with basement membrane (laminin), decreased consistent with worsened LV dilation. In vitro, ADAM15 knockdown increased cardiomyocyte hypertrophy in response to mechanical stretch. Adam15-/--TAC hearts exhibited increased calcineurin activity and de-phosphorylation of nuclear factor of activated T cells. Calcineurin inhibition (cyclosporin-A) blocked the excess hypertrophy and dilation in Adam15-/--TAC mice. Proteome profiling demonstrated the increased abundance of the key proteins linked to worsened DCM in Adam15-/--TAC.Conclusion: This is the first report demonstrating that ADAM15 can suppress hypertrophy through regulating the integrin-laminin interaction and the calcineurin pathway. [ABSTRACT FROM AUTHOR]

Introduction: The right ventricle (RV) mechanical property is an important determinant of its function. However, compared to its elasticity, RV viscoelasticity is much less studied, and it remains unclear how pulmonary hypertension (PH) alters RV viscoelasticity. Our goal was to characterize the changes in RV free wall (RVFW) anisotropic viscoelastic properties with PH development and at varied heart rates.Methods: PH was induced in rats by monocrotaline treatment, and the RV function was quantified by echocardiography. After euthanasia, equibiaxial stress relaxation tests were performed on RVFWs from healthy and PH rats at various strain-rates and strain levels, which recapitulate physiological deformations at varied heart rates (at rest and under acute stress) and diastole phases (at early and late filling), respectively.Results and Discussion: We observed that PH increased RVFW viscoelasticity in both longitudinal (outflow tract) and circumferential directions. The tissue anisotropy was pronounced for the diseased RVs, not healthy RVs. We also examined the relative change of viscosity to elasticity by the damping capacity (ratio of dissipated energy to total energy), and we found that PH decreased RVFW damping capacity in both directions. The RV viscoelasticity was also differently altered from resting to acute stress conditions between the groups—the damping capacity was decreased only in the circumferential direction for healthy RVs, but it was reduced in both directions for diseased RVs. Lastly, we found some correlations between the damping capacity and RV function indices and there was no correlation between elasticity or viscosity and RV function. Thus, the RV damping capacity may be a better indicator of RV function than elasticity or viscosity alone. These novel findings on RV dynamic mechanical properties offer deeper insights into the role of RV biomechanics in the adaptation of RV to chronic pressure overload and acute stress.

Background/Aim: The impact of myocardial stressors such as high-fat diet (HFD) and pressure overload has been extensively studied. Toll-like receptor 4 (TLR4) deficiency has been suggested to have a protective role in response to these stressors, although some conflicting data exist. Furthermore, there is limited information about the role of TLR4 on cardiac remodeling in response to long-term exposure to stressors. This study aims to investigate the effects of TLR4 deficiency on cardiac histology and physiology in response to chronic stressors. Methods: TLR4-deficient (TLR4−/−) and wild-type (WT) mice were subjected to either HFD or a normal diet (ND) for 28 weeks. Another group underwent abdominal aortic constriction (AAC) or a sham procedure and was monitored for 12 weeks. Inflammatory markers, histology, and echocardiography were used to assess the effects of these interventions. Results: TLR4−/− mice exhibited reduced cardiac hypertrophy and fibrosis after long-term HFD exposure compared to ND without affecting cardiac function. On the other hand, TLR4 deficiency worsened cardiac function in response to AAC, leading to decreased ejection fraction (EF%) and increased end-systolic volume (ESV). Conclusions: TLR4 deficiency provided protection against HFD-induced myocardial inflammation but impaired hemodynamic cardiac function under pressure overload conditions. These findings highlight the crucial role of TLR4 and its downstream signaling pathway in maintaining cardiac output during physiologic cardiac hypertrophy in response to pressure overload.