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Given the extensive participation of myeloid cells (especially monocytes and macrophages) in both inflammation and resolution phases post-myocardial infarction (MI) owing to their biphasic role, these cells are considered as crucial players in the disease pathogenesis. Multiple studies have agreed on the significant contribution of macrophage polarization theory (M2 vs. M1) while determining the underlying reasons behind the observed biphasic effects; nevertheless, this simplistic classification attracts severe drawbacks. The advent of multiple advanced technologies based on OMICS platforms facilitated a successful path to explore comprehensive cellular signatures that could expedite our understanding of macrophage heterogeneity and plasticity. While providing an overall basis behind the MI disease pathogenesis, this review delves into the literature to discuss the current knowledge on multiple macrophage clusters, including the future directions in this research arena. In the end, our focus will be on outlining the possible therapeutic implications based on the emerging observations., Competing Interests: The authors declare no competing interests., (© 2024 The Authors.)

The pathogenesis of Alzheimer's disease (AD) is complex and involves an imbalance between production and clearance of amyloid-ß peptides (Aß), resulting in accumulation of Aß in senile plaques. Hypercholesterolemia is a major risk factor for developing AD, with cholesterol shown to accumulate in senile plaques and increase production of Aß. ABCG4 is a member of the ATP-binding cassette transporters predominantly expressed in the CNS and has been suggested to play a role in cholesterol and Aß efflux from the brain. In this study, we bred Abcg4 knockout (KO) with the APP Swe,Ind (J9) mouse model of AD to test the hypothesis that loss of Abcg4 would exacerbate the AD phenotype. Unexpectedly, no differences were observed in novel object recognition (NOR) and novel object placement (NOP) behavioral tests, or on histologic examinations of brain tissues for senile plaque numbers. Furthermore, clearance of radiolabeled Aß from the brains did not differ between Abcg4 KO and control mice. Metabolic testing by indirect calorimetry, glucose tolerance test (GTT), and insulin tolerance test (ITT) were also mostly similar between groups with only a few mild metabolic differences noted. Overall, these data suggest that the loss of ABCG4 did not exacerbate the AD phenotype., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Pyroptosis executor GsdmD (gasdermin D) promotes atherosclerosis in mice and humans. Disulfiram was recently shown to potently inhibit GsdmD, but the in vivo efficacy and mechanism of disulfiram's antiatherosclerotic activity is yet to be explored., Methods and Results: We used human/mouse macrophages, endothelial cells, and smooth muscle cells and a hyperlipidemic mouse model of atherosclerosis to determine disulfiram antiatherosclerotic efficacy and mechanism. The effects of disulfiram on several atheroprotective pathways such as autophagy, efferocytosis, phagocytosis, and gut microbiota were determined. Atomic force microscopy was used to determine the effects of disulfiram on the biophysical properties of the plasma membrane of macrophages. Disulfiram-fed hyperlipidemic apolipoprotein E -/- mice showed significantly reduced interleukin-1β release upon in vivo Nlrp3 (NLR family pyrin domain containing 3) inflammasome activation. Disulfiram-fed mice showed smaller atherosclerotic lesions (~27% and 29% reduction in males and females, respectively) and necrotic core areas (~50% and 46% reduction in males and females, respectively). Disulfiram induced autophagy in macrophages, smooth muscle cells, endothelial cells, hepatocytes/liver, and atherosclerotic plaques. Disulfiram modulated other atheroprotective pathways (eg, efferocytosis, phagocytosis) and gut microbiota. Disulfiram-treated macrophages showed enhanced phagocytosis/efferocytosis, with the mechanism being a marked increase in cell-surface expression of efferocytic receptor MerTK. Atomic force microscopy analysis revealed altered biophysical properties of disulfiram-treated macrophages, showing increased order-state of plasma membrane and increased adhesion strength. Furthermore, 16sRNA sequencing of disulfiram-fed hyperlipidemic mice showed highly significant enrichment in atheroprotective gut microbiota Akkermansia and a reduction in atherogenic Romboutsia species., Conclusions: Taken together, our data show that disulfiram can simultaneously modulate several atheroprotective pathways in a GsdmD-dependent as well as GsdmD-independent manner.

Of all the different risk factors known to cause cardiovascular disease (CVD), age and sex are considered to play a crucial role. Aging follows a continuum from birth to death, and therefore it inevitably acts as a risk for CVD. Along with age, sex differences have also been shown to demonstrate variations in immune system responses to pathological insults. It has been widely perceived that females are protected against myocardial infarction (MI) and the protection is quite apparent in young vs. old women. Acute MI leads to changes in the population of myeloid and lymphoid cells at the injury site with myeloid bias being observed in the initial inflammation and the lymphoid in the late-resolution phases of the pathology. Multiple evidence demonstrates that aging enhances damage to various cellular processes through inflamm-aging, an inflammatory process identified to increase pro-inflammatory markers in circulation and tissues. Following MI, marked changes were observed in different sub-sets of major myeloid cell types viz., neutrophils, monocytes, and macrophages. There is a paucity of information regarding the tissue and site-specific functions of these sub-sets. In this review, we highlight the importance of age and sex as crucial risk factors by discussing their role during MI-induced myelopoiesis while emphasizing the current status of myeloid cell sub-sets. We further put forth the need for designing and executing age and sex interaction studies aimed to determine the appropriate age and sex to develop personalized therapeutic strategies post-MI., Competing Interests: Declaration of Competing Interest The authors report no declarations of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Smoking is one of the most prominent addictions of the modern world, and one of the leading preventable causes of death worldwide. Although the number of tobacco smokers is believed to be at a historic low, electronic cigarette use has been on a dramatic rise over the past decades. Used as a replacement for cigarette smoking, electronic cigarettes were thought to reduce the negative effects of burning tobacco. Nonetheless, the delivery of nicotine by electronic cigarettes, the most prominent component of cigarette smoke (CS) is still delivering the same negative outcomes, albeit to a lesser extent than CS. Smoking has been shown to affect both the structural and functional aspects of major organs, including the lungs and vasculature. Although the deleterious effects of smoking on these organs individually is well-known, it is likely that the adverse effects of smoking on these organs will have long-lasting effects on the cardiovascular system. In addition, smoking has been shown to play an independent role in the homeostasis of the immune system, leading to major sequela. Both the adaptive and the innate immune system have been explored regarding CS and have been demonstrated to be altered in a way that promotes inflammatory signals, leading to an increase in autoimmune diseases, inflammatory diseases, and cancer. Although the mechanism of action of CS has not been fully understood, disease pathways have been explored in both branches of the immune system. The pathophysiologically altered immune system during smoking and its correlation with cardiovascular diseases is not fully understood. Here we highlight some of the important pathological mechanisms that involve cigarette smoking and its many components on cardiovascular disease and the immune systems in order to have a better understanding of the mechanisms at play.

Smith-Lemli-Opitz Syndrome (SLOS) is a developmental disorder (OMIM #270400) caused by autosomal recessive mutations in the Dhcr7 gene, which encodes the enzyme 3β-hydroxysterol-Δ7 reductase. SLOS patients present clinically with dysmorphology and neurological, behavioral, and cognitive defects, with characteristically elevated levels of 7-dehydrocholesterol (7-DHC) in all bodily tissues and fluids. Previous mouse models of SLOS have been hampered by postnatal lethality when Dhcr7 is knocked out globally, while a hypomorphic mouse model showed improvement in the biochemical phenotype with aging and did not manifest most other characteristic features of SLOS. We report the generation of a conditional knockout of Dhcr7 (Dhcr7 flx/flx ), validated by generating a mouse with a liver-specific deletion (Dhcr7 L-KO ). Phenotypic characterization of liver-specific knockout mice revealed no significant changes in viability, fertility, growth curves, liver architecture, hepatic triglyceride secretion, or parameters of systemic glucose homeostasis. Furthermore, qPCR and RNA-Seq analyses of livers revealed no perturbations in pathways responsible for cholesterol synthesis, either in male or in female Dhcr7 L-KO mice, suggesting that hepatic disruption of postsqualene cholesterol synthesis leads to minimal impact on sterol metabolism in the liver. This validated conditional Dhcr7 knockout model may now allow us to systematically explore the pathophysiology of SLOS, by allowing for temporal, cell and tissue-specific loss of DHCR7., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Published by Elsevier Inc.)

The enzyme 3β-hydroxysterol-Δ24 reductase (DHCR24, EC 1.3.1.72) catalyzes the conversion of desmosterol to cholesterol and is obligatory for post-squalene cholesterol synthesis. Genetic loss of this enzyme results in desmosterolosis (MIM #602398), a rare disease that presents with multiple congenital anomalies, features of which overlap with subjects with the Smith-Lemli-Opitz syndrome (another post-squalene cholesterol disorder). Global knockout (KO) of Dhcr24 in mice recapitulates the biochemical phenotype, but pups die within 24 h from a lethal dermopathy, limiting its utility as a disease model. Here, we report a conditional KO mouse model (Dhcr24 flx/flx ) and validate it by generating a liver-specific KO (Dhcr24 flx/flx,Alb-Cre ). Dhcr24 flx/flx,Alb-Cre mice showed normal growth and fertility, while accumulating significantly elevated levels of desmosterol in plasma and liver. Of interest, despite the loss of cholesterol synthesis in the liver, hepatic architecture, gene expression of sterol synthesis genes, and lipoprotein secretion appeared unchanged. The increased desmosterol content in bile and stool indicated a possible compensatory role of hepatobiliary secretion in maintaining sterol homeostasis. This mouse model should now allow for the study of the effects of postnatal loss of DHCR24, as well as role of tissue-specific loss of this enzyme during development and adulthood., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Published by Elsevier Inc.)

Background: Autosomal dominant familial hypercholesterolemia (ADH; MIM#143890) is one of the most common monogenic disorders characterized by elevated circulatory LDL cholesterol. Initial studies in humans with ADH identified a potential relationship with variants of the gene encoding signal transducing adaptor family member protein 1 (STAP1; MIM#604298). However, subsequent studies have been contradictory. In this study, mice lacking global Stap1 expression (Stap1 -/- ) were characterized under standard chow and a 42% kcal western diet (WD)., Methods: Mice were studied for changes in different metabolic parameters before and after a 16-week WD regime. Growth curves, body fats, circulatory lipids, parameters of glucose homeostasis, and liver architecture were studied for comparisons., Results: Surprisingly, Stap1 -/- mice fed the 16-week WD demonstrated no marked differences in any of the metabolic parameters compared to Stap1 +/+ mice. Furthermore, hepatic architecture and cholesterol content in FPLC-isolated lipoprotein fractions also remained comparable to wild-type mice., Conclusion: These results strongly suggest that STAP1 does not alter lipid levels, that a western diet did not exacerbate a lipid disorder in Stap1 deficient mice and support the contention that it is not causative for hyperlipidemia in ADH patients. These results support other published studies also questioning the role of this locus in human hypercholesterolemia.

Recent study from this lab indicated enhanced susceptibility of iNOS KO mice for diet induced obesity (DIO) and systemic insulin resistance (IR) as compared to C57BL/6 (WT) mice. The present study investigates aortic vasoreactivity in high fat diet (HFD) induced insulin resistant iNOS KO mice. WT and iNOS KO mice were fed with 45% HFD/10% LFD for ten weeks. Systemic IR was assessed via measurement of circulating lipids, glucose, and insulin; while phenylephrine (PE)/acetylcholine (ACh) induced responses were monitored in the isolated aortic rings. To understand the mechanism, qPCR or Western blotting experiments were performed in aorta and Ea.hy926 cells. After 10 weeks of HFD feeding, significant increase in the body weight/fat mass, augmented circulating lipids, glucose, insulin and inflammatory cytokines along with impaired acetylcholine induced aortic vasorelaxation and enhanced iNOS expression was observed in the aortic tissue of WT mice. In the aminoguanidine (AG, 20 mg/kg for 4 weeks) treated WT mice and also in iNOS KO mice, acetylcholine induced vasorelaxation was significantly preserved. Further, acetylcholine mediated vasorelaxation correlated with increased eNOS phosphorylation at Ser1177 residue in the iNOS KO mice and same was also observed in the iNOS silenced Ea.hy926 cells. Moreover, treatment of Ea.hy926 cells with palmitic acid or TNFα also caused a significant decrease in eNOS activity, which was reversed in iNOS silenced Ea.hy926 cells suggesting the role of iNOS in the reduction of eNOS activity. The study thus implies a critical role of iNOS in vascular diseases associated with dyslipidemia/IR., (Copyright © 2019. Published by Elsevier B.V.)