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During a heart attack, ischemia causes losses of billions of cells; this is especially concerning given the minimal regenerative capability of cardiomyocytes (CMs). Heart remuscularization utilizing stem cells has improved cardiac outcomes despite little cell engraftment, thereby shifting focus to cell-free therapies. Consequently, we chose induced pluripotent stem cells (iPSCs) given their pluripotent nature, efficacy in previous studies, and easy obtainability from minimally invasive techniques. Nonetheless, using iPSC secretome-based therapies for treating injured CMs in a clinical setting is ill-understood. We hypothesized that the iPSC secretome, regardless of donor health, would improve cardiovascular outcomes in the CM model of ischemia–reperfusion (IR) injury. Episomal-generated iPSCs from healthy and dilated cardiomyopathy (DCM) donors, passaged 6–10 times, underwent 24 h incubation in serum-free media. Protein content of the secretome was analyzed by mass spectroscopy and used to treat AC16 immortalized CMs during 5 h reperfusion following 24 h of hypoxia. IPSC-derived secretome content, independent of donor health status, had elevated expression of proteins involved in cell survival pathways. In IR conditions, iPSC-derived secretome increased cell survival as measured by metabolic activity (p < 0.05), cell viability (p < 0.001), and maladaptive cellular remodelling (p = 0.052). Healthy donor-derived secretome contained increased expression of proteins related to calcium contractility compared to DCM donors. Congruently, only healthy donor-derived secretomes improved CM intracellular calcium concentrations (p < 0.01). Heretofore, secretome studies mainly investigated differences relating to cell type rather than donor health. Our work suggests that healthy donors provide more efficacious iPSC-derived secretome compared to DCM donors in the context of IR injury in human CMs. These findings illustrate that the regenerative potential of the iPSC secretome varies due to donor-specific differences. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19), an acute and highly transmissible infectious disease, has reached a pandemic level since 11 March 2020 and continues to challenge the healthcare system worldwide. The pathogenesis of COVID-19 is a complex process involving mechanisms that suppress the host antiviral and innate immune response, while triggering marked activation of coagulation and hyperinflammation leading to cytokine storm in severe COVID-19. This review summarizes current evidence related to COVID-19-associated cardiovascular severe illness and mortality, which encompasses life-threatening clinical manifestations, including myocardial injury, fulminant myocarditis, cardiac arrhythmia, and ischemic stroke. The onset of hypercoagulable state is consistent with increased venous thromboembolism including deep vein thrombosis and pulmonary embolism. Thromboembolic manifestations include arterial thrombotic events such as stroke, myocardial infarction, and limb ischemia. Several treatment strategies have been investigated to mitigate COVID-19-associated cardiovascular clinical manifestations. The prevalence of thrombo-inflammatory syndrome and subsequent cardiovascular dysfunction prompted the implementation of antithrombotic therapy and strategies targeting major pro-inflammatory cytokines involved in COVID-19 cytokine storm. The development of new guidelines for effective treatment strategies requires concerted efforts to refine our understanding of the mechanisms underlying cardiovascular disease and large-scale clinical trials to reduce the burden of COVID-19 hospitalization and mortality. Key words: COVID-19, cardiovascular system, treatments. La maladie a coronavirus 2019 (COVID-19), maladie infectieuse aigue et hautement transmissible, a atteint le degre de pandemie depuis le 11 mars 2020 et continue a menacer le systeme de sante a l'echelle mondiale. La pathogenese de la COVID-19 constitue un processus complexe mettant en jeu des modes d'action qui inhibent la reaction antivirale et immunitaire innee de l'hote, tout en declenchant une activation de la coagulation et une hyperinflammation menant a un orage de cytokines dans la forme grave de la maladie. Cet article de synthese resume les donnees probantes actuelles quant aux atteintes graves et a la mortalite de nature cardiovasculaire, ce qui comprend des manifestations cliniques menacant le pronostic vital, y compris les lesions myocardiques, la myocardite fulminante, les arythmies cardiaques et l'AVC ischemique. L'avenement d'un etat d'hypercoagulabilite s'inscrit dans un contexte d'accroissement des thromboembolies veineuses, y compris la thrombose veineuse profonde et l'embolie pulmonaire. Les manifestations thromboemboliques comprennent des evenements thrombotiques arteriels comme l'AVC, l'infarctus du myocarde et l'ischemie des extremites. On a etudie plusieurs strategies de traitement en vue d'attenuer les manifestations cliniques cardiovasculaires associees avec la COVID-19. La frequence du syndrome thrombo-inflammatoire et du dysfonctionnement cardiovasculaire subsequent a justifie l'emploi de traitements antithrombotiques et de strategies ciblant les principales cytokines proinflammatoires jouant un role dans l'orage de cytokines de la COVID-19. La mise au point de nouvelles lignes directrices pour des strategies de traitement efficaces exige des efforts concertes pour raffiner notre comprehension des modes d'action de la maladie cardiovasculaire sous-jacente de meme que la mise en place d'essais cliniques a grande echelle en vue de reduire le fardeau de la COVID-19 en matiere d'hospitalisations et de mortalite. [Traduit par la Redaction] Mots-cles: COVID-19, systeme cardiovasculaire, traitements., Introduction The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak has devastated the global population, taking the lives of millions of people and changing life as we know it. In [...]

The cellular mechanisms that induce calcific aortic stenosis are yet to be unraveled. Wnt signaling is increasingly being considered as a major player in the disease process. However, the presence of Wnt Frizzled (Fzd) receptors and co-receptors LRP5 and 6 in normal and diseased human aortic valves remains to be elucidated. Immunohistochemistry and quantitative polymerase chain reaction were used to determine Fzd receptor expression in normal and calcified human aortic valve tissue, as well as human aortic valve interstitial cells (HAVICs) isolated from calcified and normal human aortic valves. There was significantly higher mRNA expression of 4 out of the 10 Fzd receptors in calcified aortic valve tissues and 8 out of the 10 in HAVICs, and both LRP5/6 co-receptors in calcified aortic valves (P < 0.05). These results were confirmed by immunohistochemistry, which revealed abundant increase in immunoreactivity for Fzd3,7, and 8, mainly in areas of lipid core and calcified nodules of diseased aortic valves. The findings of abundant expression of Fzd and LRP5/6 receptors in diseased aortic valves suggests a potential role for both canonical and noncanonical Wnt signaling in the pathogenesis of human aortic valve calcification. Future investigations aimed at targeting these molecules may provide potential therapies for aortic valve stenosis. Key words: Wnt, LRP, disease, aortic valve stenosis, mRNA, protein, qPCR, immunohistochemistry. Les modes d'action cellulaires qui engendrent la stenose aortique calcifiee demeurent a eclaircir. On considere de plus en plus que la voie de signalisation des proteines Wnt joue un role majeur dans le processus pathologique. Cependant, la presence de recepteurs Fzd (pour<>) et de corecepteurs LRP5 et 6 dans les valvules aortiques humaines normales et pathologiques demeure a elucider. A l'aide de techniques d'immunohistochimie et d'amplification en chaine par polymerase quantitative (qPCR), nous avons tente d'etablir l'expression des recepteurs Fzd dans du tissu de valvules aortiques humaines normales et calcifiees, ainsi que dans des cellules interstitielles de valvules aortiques humaines (CIVAH) isolees de valvules aortiques humaines normales et calcifiees. Nous avons observe une augmentation de l'expression (i) de l'ARNm de 4 des 10 recepteurs Fzd dans le tissu de valvules aortiques calcifiees et de 8 de ces 10 recepteurs dans les CIVAH, ainsi que (ii) des corecepteurs LRP5 comme 6 dans les valvules aortiques calcifiees (P < 0,05). Nous avons confirme ces resultats a l'aide de techniques immunohistochimiques, qui ont revele la presence d'une importante augmentation de l'immunoreactivite contre les recepteurs Fzd3, 7 et 8, principalement aux endroits ou les valvules aortiques pathologiques presentaient des noyaux lipidiques et des nodules calcifies. Ces resultats montrant une importante augmentation de l'expression de recepteurs Fzd et LRP5/6 dans les valvules aortiques pathologiques laissent entendre que les voies de signalisation canoniques comme non canoniques des proteines Wnt pourraient jouer un role dans la pathogenese de la calcification des valvules aortiques humaines. Des etudes futures portant sur le ciblage de ces molecules pourraient permettre de decouvrir des traitements eventuels contre la stenose de l'appareil valvulaire aortique. [Traduit par la Redaction] Mots-cles: proteine Wnt, LRP, maladie, stenose de l'appareil valvulaire aortique, ARNm, proteine, qPCR, immunohistochimie., Introduction Aortic stenosis is the most prevalent valvular heart disease in developed countries, affecting 0.2% of adults between the ages of 50 and 59 years, and 2.8% of adults older [...]

Aims The biogenesis of high-density lipoprotein (HDL) particles by cholesterol-laden foam cells in atherosclerotic lesions is crucial for the removal of excess cholesterol from the lesions. Impairment in the HDL biogenic process contributes to the progression of atherosclerosis. The aim of this study is to identify novel cellular factors regulating HDL biogenesis. Methods and results HDL biogenesis is a process of apolipoprotein (apo)-mediated solubilization of specific plasma membrane (PM) microdomains generated in cholesterol-accumulated cells. We established a new method to isolate PM microdomains interacting with the major HDL protein constituent, apoA-I. Lipidomic and proteomic analyses of an isolated PM microdomain revealed that apoA-I binds to cholesterol-rich and desmocollin 1 (DSC1)-containing microdomains. In this novel apoA-I binding microdomain, DSC1 binds and prevents apoA-I from interacting with another PM microdomain created by adenosine triphosphate-binding cassette transporter A1 (ABCA1) for the formation of HDL. Inhibition of apoA-I-DSC1 binding by silencing DSC1 expression or using DSC1 blocking antibodies increases apoA-I accessibility to ABCA1-created microdomains and thus enhances HDL biogenesis. Importantly, DSC1 is abundantly expressed in macrophages and human atherosclerotic lesions, suggesting that DSC1 may contribute to cholesterol accumulation in atherosclerotic lesions by sequestering apoA-I and impairing HDL biogenesis. Conclusions The binding of apoA-I to two functionally opposing PM microdomains, ABCA1 and DSC1 domains, suggests that HDL biogenesis and PM cholesterol levels may be regulated by the relative abundance of the two domains and that novel HDL biogenic therapies may be developed by targeting DSC1. [ABSTRACT FROM AUTHOR]