Search

Supplemental Digital Content is Available in the Text., Ischemia and anoxia-induced mitochondrial impairment may be a key factor leading to heart injury during myocardial infarction (MI). Calpain 1 and 2 are involved in the MI-induced mitochondria injury. G protein-coupled receptor 35 (GPR35) could be triggered by hypoxia. Whether or not GPR35 regulates calpain 1/2 in the pathogenesis of MI is still unclear. In this study, we determined that MI increases GPR35 expression in myocardial tissue. Suppression of GPR35 protects heart from MI injury in mice through reduction of reactive oxygen species activity and mitochondria-dependent apoptosis. Further studies show that GPR35 regulates calpain 1/2. Suppression of GPR35 reduces the expression and activity of calpain 1/2, and alleviates calpain 1/2-associated mitochondrial injury to preserve cardiac function. Based on these data, we conclude that a functional inhibition of GPR35 downregulates calpain 1/2 and contributes to maintenance of cardiac function under pathologic conditions with mitochondrial disorder. In conclusion, our study showed that the identified regulation by GPR35 of calpain 1/2 has important implications for the pathogenesis of MI. Targeting the action of GPR35 and calpain 1/2 in mitochondria presents a potential therapeutic intervention for MI.

Transient receptor potential vanilloid type 1 (TRPV1) is a nonselective cation channel that mediates the relationship between mitochondrial function and pathological myocardial hypertrophy. However, its underlying mechanisms remain unclear. This study aimed to investigate whether TRPV1 activation improves the morphology and function of intracellular mitochondria to protect cardiomyocytes after pressure overload-induced myocardial hypertrophy. The myocardial hypertrophy model was established by performing transverse aortic constriction surgery in C57BL/6 J male mice. The data revealed that TRPV1 activation significantly reduced myocardial hypertrophy, promoted ejection fraction% and fractional shortening%, and decreased the left ventricular internal diameter in end-diastole and left ventricular internal diameter in end-systole after transverse aortic constriction. Moreover, in vitro experiments revealed that TRPV1 reduces cardiomyocyte area and improves mitochondrial function by promoting mitochondria-associated endoplasmic reticulum membranes (MAMs) formation in a phenylephrine-treated cardiomyocyte hypertrophy model. TRPV1 up-regulates the phosphorylation levels of AMP-activated protein kinase and expression of mitofusin2 (MFN2). TRPV1 function is blocked by single-stranded RNA interfering with silent interfering MFN2. Activation of TRPV1 reduced mitochondrial reactive oxygen species caused by phenylephrine, whereas disruption of MAMs by siMFN2 abolished TRPV1-mediated mitochondrial protection. Our findings suggest that TRPV1 effectively protects against pressure overload-induced cardiac hypertrophy by promoting MAM formation and conserved mitochondrial function via the AMP-activated protein kinase/MFN2 pathway in cardiomyocytes.

Microvascular protection is the main mechanism of metformin against diabetic complications. Cardiac microvascular endothelial cells (CMECs) are the basic component of cardiac microvessels, and they suffer from oxidative stress and mitochondrial dysfunction under type 2 diabetes mellitus (T2DM). Translocase of the outer mitochondrial membrane 70 (Tom70) improves mitochondrial dysfunction, but its role in the hearts of T2DM patients remains unclear. The purpose of this study was to demonstrate the protective effect of metformin on diabetic cardiac microvascular injury and to identify the role of Tom70 in this effect. T2DM mice were established by multiple intraperitoneal injections of low-dose streptozotocin and 12-week high-fat feeding. CMECs were isolated and cultured with normal glucose (NG), high glucose (HG), and HG plus high fat (HG-HF) media. The results indicated that long-term metformin treatment partly reversed cardiovascular complication and mitigated cardiac microvascular injury in T2DM. In addition, exposure to HG-HF led to CMEC damage, aggravated oxidative stress, aggravated mitochondrial dysfunction, and reduced mitochondrial Tom70 expression, whereas upregulation of Tom70 significantly ameliorated these injuries. Furthermore, metformin treatment promoted Tom70 expression and effectively reversed CMEC injury induced by HG-HF. However, all of these effects were interrupted after Tom70 was knocked down. In conclusion, T2DM damages microvascular integrity by activating a cycle of decreased Tom70 expression, mitochondrial dysfunction, and reactive oxygen species (ROS) overload in CMECs. However, metformin suppresses oxidative stress, relieves mitochondrial dysfunction, and promotes the expression of Tom70, ultimately ameliorating diabetic microvascular injury and heart complications.

Vascular restenosis badly harms the curative effect of revascularization, despite the fact that novel treatments especially percutaneous interventions of coronary, carotid and other peripheral arteries have made great progress over the past 20 years [1,2]. Therefore, revealing the underlying mechanisms and searching for novel therapeutic targets of restenosis are to be urgently solved. The initiating step of vascular restenosis is de-endothelization and compression of atherosclerotic plaque into vascular wall via mechanical injury [3]. Whereafter, activated platelet and inflammatory cells gather at damaged area and secrete several cytokines, such as platelet-derived growth factor (PDGF), interleukin-6 and interleukin-1β, and so forth [3]. These processes initiate subsequent proliferation and migration of vascular smooth muscle cells (VSMCs) and lead to neointima hyperplasia, vascular remodeling and restenosis [3]. As the major components of vascular wall, VSMCs play a crucial role in maintaining normal function of blood vessels (e.g. self-repairment) but also in neointima formation owing to the high proliferative activity [4]. Accordingly, preventing excessive VSMC proliferation is emerging as a potent method for restenosis treatment. Numerous studies have shown that, in mammalian bodies, VSMCs maintain a balance between proliferation and apoptosis. Under certain pathological conditions, VSMCs switch to a synthetic growth phenotype, which is characterized by excessive proliferation and migration [5,6]. The contractile-to-synthetic growth transition is a multifactorial process that involves many signaling pathways including cytokines, protein kinases, transcription factors and regulatory RNA molecules, and so forth. Though treatments based on aforementioned pathways, such as phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) pathways, a classical pathway regulating VSMC proliferation [7,8], have been introduced, the morbidity of restenosis still reached 10% [2]. Therefore, unraveling the novel underlying mechanism regulating VSMC proliferation is of great significance for preventing vascular restenosis. The wild-type p53-induced phosphatase 1 (Wip1), a member of the PP2C family of Ser/Thr protein phosphatases, is also addressed as protein phosphatase magnesium-dependent 1 delta (PPM1D) [9]. Overexpressed in various tumors, Wip1 is originally emerging as an oncogene regulating tumorigenesis via its regulation of apoptosis [10,11]. At the molecular level, regulation of ATM in the mammalian target of rapamycin (mTOR) and P53 is discovered to play a key role in Wip1-mediated tumorigenesis [12]. Many studies have found that Wip1 also participates in other biological processes, such as neurogenesis [13], organismal aging [14] and haematopoietic stem cell homeostasis [15]. Wip1 is recently discovered to exert a pro-atherosclerotic role in the pathological process of atherosclerosis, during which autophagy, cholesterol efflux and macrophage migration are involved [16,17]. In the above study, adenosine 5′-monophosphate-activated protein kinase (AMPK) is also confirmed to be involved in ATM-dependent regulation of mTOR [16]. Vascular restenosis has similar pathological processes to atherosclerosis, such as VSMC proliferation and migration [18], reminding us that Wip1 may also be a potent functional regulator in vascular restenosis. However, whether Wip1 is associated with VSMC proliferation, neointima hyperplasia and restenosis after vascular injury is largely unknown. In the current study, we describe a regulatory role for Wip1 in vascular restenosis, in which AMPK/mTORC1 pathway is involved. By using a Wip1 antagonist GSK2830371 (GSK), we found that Wip1 inhibition suppresses VSMC proliferation and neointima hyperplasia, accompanied by enhanced AMPK phosphorylation and decreased mTORC1 activity. Further study shows GSK fails to prevent VSMC proliferation and neointima hyperplasia in mice with tuberous sclerosis 1 (TSC1) knockdown, and thus leading to enhanced restenosis. Our research shows that Wip1-dependent modulation of VSMC proliferation and neointima hyperplasia by means of AMPK/mTORC1 may be identified as a potential therapeutic intervention for vascular restenosis.

Background: As a public health emergency of international concern, the COVID-19 outbreak has had a tremendous impact on patients' psychological health. However, studies on psychological interventions in patients with COVID-19 are relatively rare.Objectives: This study examined the effectiveness of Cognitive Behavioral Therapy (CBT) in relieving patients' psychological distress during the COVID-19 epidemic.Methods: Ninety-three eligible participants selected by cluster sampling were randomized to an intervention group (N = 47) and a control group (N = 46). Participants in the control group received routine treatment according to the Chinese Management Guidelines for COVID-19, while participants in the intervention group received routine treatment with additional CBT. The Chinese Version of Depression Anxiety and Stress Scale-21 (DASS-21) was used to evaluate depression, anxiety, and stress for all participants at baseline and post-intervention. Two-sided t-test, and proportion tests were used to examine the differences between the intervention and control group for each DASS-21 indicator. Univariate linear regression was used to examine the association between chronic disease status and change in each DASS-21 indicator after intervention. Two-way scatter plots were generated to show the association of the length of hospital stay and the changes of each DASS-21 indicator by intervention and control groups.Results: Significant decreases in means were found for scales of depression, anxiety, stress and total DASS-21 in both intervention (p < 0.001) and control group (p = 0.001), with participants in the intervention group having a bigger reduction in means. After the intervention, more participants in the intervention group had no depression or anxiety symptoms than in the control group, but no statistical differences were found (p > 0.05). Compared with participants with chronic disease, participants with no chronic disease had a significantly larger reduction of total DASS-21 scale (coefficient = −4.74, 95% CI: −9.31; −0.17).The length of hospital stay was significantly associated with a greater increase in anxiety scale in the intervention group (p = 0.005), whilst no significant association was found in the control group (p = 0.29).Conclusions: The patients with COVID-19 experienced high levels of anxiety, depression and stress. Our study result highlights the effectiveness of CBT in improving the psychological health among patients with COVID-19, also suggests that CBT should be focused on patients with chronic disease and those who have longer hospital stays. These results have important implications in clinical practice in improving psychological health in the context of COVID-19 pandemic.Trial Registration: ISRCTN68675756. Available at: http://www.isrctn.com/ISRCTN68675756.

Aims To evaluate psychological well-being and factors associated with post-traumatic stress disorder (PTSD) among front-line nurses during the coronavirus disease-2019 (COVID-19) pandemic. Background Coronavirus disease-2019 is a pandemic that has posed a public health emergency of international concern. Psychological well-being of front-line nurses is a big concern during the COVID-19 pandemic. Methods With a predictive study design, a same survey was sent separately at two time points (i.e. before and after nurses worked at COVID-19 units) between January and March 2020 among 356 front-line nurses in First Affiliated Hospital of Bengbu Medical College, Anhui, China. Results Of a total 356 front-line nurses, stress level and the prevalence of PTSD were significantly increased after they worked at COVID-19 units. Nurses who had work experience less than 2 years were significantly associated with a high risk of developing PTSD. Nurses who worked in COVID-19 inpatients wards had significantly higher odds of being PTSD (odds ratio [OR] = 21.9, 95% confidence interval [CI]: 5.08; 94.5) than those who worked in other COVID-19-related units. Resilience was negatively associated with PTSD (OR = 0.96, 95% CI: 0.93; 0.99). Conclusion Nurses had significantly increased risk to develop PTSD during COVID-19 pandemic. Implications for nursing management Clinical and policy strategies to support front-line nurses' psychological well-being, particularly young nurses, in response to COVID-19 crisis are urgently needed.

Cardiac microvascular injury often occurs in patients with type 2 diabetes mellitus (T2DM) who develop hyperglycemia and hyperlipidemia. However, besides reported contradictory roles in cardiac diseases, the function of TRPV1 (transient receptor potential vanilloid 1) in cardiac microvessels is not well defined. This study was performed to determine the detailed role of TRPV1 in cardiac microvascular endothelial cells (CMECs) in T2DM. T2DM mice were established by multiple injections of low-dose streptozotocin and high-fat feeding. CMECs were cultured separately in mediums of normal glucose, high glucose (HG), high fatty acid (HF), and HG plus HF (HG-HF). HG-HF inhibited TRPV1 expression in CMECs, reducing cellular Ca 2+ content ([Ca 2+ ] i ). T2DM impaired cardiac function, disturbed glucose uptake, and damaged microvascular barrier, which were further aggravated by TRPV1 −/− . Exposure to HG-HF, particularly in TRPV1 −/− CMECs, led to a higher level of apoptosis and a lower level of nitric oxide production in viable CMECs. HG-HF markedly enhanced generation of reactive oxygen species and nitrotyrosine, especially in the absence of TRPV1. H 2 O 2 administration reduced TRPV1 expression in CMECs. HG-HF significantly depressed expression of PGC-1α (peroxisome proliferator–activated receptor-γ coactivator-1α) and OPA1 (optic atrophy 1) by reducing [Ca 2+ ] i , whereas OPA1 supplementation partly reversed those detrimental effects induced by TRPV1 −/− . Furthermore, capsaicin treatment not only attenuated CMECs injury induced by HG-HF but also mitigated cardiac microvascular injury induced by T2DM. Collectively, T2DM leads to cardiac microvascular injury by exacerbating the vicious circle of TRPV1 blockage and reactive oxygen species overload. Long-term capsaicin can protect cardiac microvessels against T2DM via suppressing oxidative/nitrative stress mediated by TRPV1/Ca 2+ /PGC-1α/OPA1 pathway in CMECs.

Ischemic heart diseases (IHD) have become the leading cause of death around the world, killing more than 7 million people annually. In IHD, the blockage of coronary vessels will cause irreversible cell injury and even death. As the “powerhouse” and “apoptosis center” in cardiomyocytes, mitochondria play critical roles in IHD. Ischemia insult can reduce myocardial ATP content, resulting in energy stress and overproduction of reactive oxygen species (ROS). Thus, mitochondrial abnormality has been identified as a hallmark of multiple cardiovascular disorders. To date, many studies have suggested that these mitochondrial proteins, such as electron transport chain (ETC) complexes, uncoupling proteins (UCPs), mitochondrial dynamic proteins, translocases of outer membrane (Tom) complex, and mitochondrial permeability transition pore (MPTP), can directly or indirectly influence mitochondria-originated ROS production, consequently determining the degree of mitochondrial dysfunction and myocardial impairment. Here, the focus of this review is to summarize the present understanding of the relationship between some mitochondrial functional proteins and ROS production in IHD.

As one main active compound of curcuminoids, Bisdemethoxycurcumin (BDMC) possesses several biological activities, such as anti-inflammation and anti-cancer activities. However, the detailed mechanism of BDMC’s anti-metastasis activity in ovarian cancer has not been clearly elucidated yet. In the present study, cell proliferation, wound healing motility, cell adhesion and invasion with or without BDMC were determined. In addition, western blot was used to examine proteins expressions. The lucigenin-enhanced luminescence was introduced to assess cellular oxidative stress. The luciferase reporter gene assay was introduced to evaluate the transcriptional activity of NF-κB. Finally, BDMC significantly inhibited the adhesion, migration, invasion and metastasis of SKOV-3 cells. Moreover, BDMC inhibited expressions of several degradation-associated proteins, such as matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), CD147, urokinase plasminogen activator (uPA), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), whereas increased expression of tissue inhibitor of metalloproteinase-1 (TIMP-1), in a dose-dependent manner. In addition, BDMC reduced generation of cellular superoxide in a dose-dependent manner. Furthermore, BDMC inhibited the phosphorylation levels of NF-κB p65 and IκB-α and consequently reduced NF-κB-driven luciferase expression. Collectively, BDMC serves as a therapeutic medicine to suppress ovarian cancer, perhaps via inhibiting cellular oxidative stress and subsequently inactivating NF-κB pathway.

Increased oxidative stress is involved in the development of vascular dysfunction and remodeling. Uncoupling protein 2 (UCP2) regulates the production of reactive oxygen species in vascular smooth muscle cells (SMCs). To promote the study of the role of UCP2 in vascular diseases, a transgenic mouse model expressing human UCP2 (hUCP2) in vascular SMCs was established. We constructed a plasmid carrying the 2.3 kb rabbit smooth muscle myosin heavy chain promoter and the hUCP2 gene. We used this plasmid to produce transgenic mice by pro-nuclear microinjection. Six offspring were identified as founder mice that were used to establish a transgenic mouse lineage. The transgenic mice showed a significant increase in hUCP mRNA expression in the aorta. Moreover, hUCP2 overexpression inhibited the production of superoxide and increased the bioavailability of nitric oxide (NO). In this study, we established a hUCP2 transgenic mouse model, which will enable further studies on the role of UCP2 in vascular dysfunction and remodeling.

The cold weather is associated with an increased occurrence of acute coronary events. However, the mechanisms underlying cold‑induced myocardial infarctions have not yet been fully elucidated. In the present study, 20 male, eight week‑old, apolipoprotein E (ApoE)‑deficient mice were subjected to either control conditions or intermittent cold exposure for eight weeks. Mice in the cold group were placed in a cold room at 4˚C for 4 h per day, while the mice in the control group were kept in a room at 24˚C. Cold‑exposed mice did not significantly differ from control mice in body weight, fasting glucose concentration and plasma lipid levels, including triglyceride, total cholesterol, low‑density lipoprotein and high‑density lipoprotein. The hematoxylin and eosin‑stained sections of the aortic root demonstrated increased plaque size in the cold group compared with the control group (P