acase@tulane.edu

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Das severe acute respiratory syndrome Coronavirus (SARS-CoV) ist ein hochpathogenes Virus, dessen zoonotischer Eintrag in die Bevölkerung eine substantielle Gesundheitsgefahr darstellt. Die Identifizierung von Wirtszellfaktoren, die für die SARS-CoV-Ausbreitung und Pathogenese wichtig sind, könnte neue Ansatzpunkte für die Therapie liefern. Das SARS-CoV-Oberflächenprotein Spike (S) bindet an den zellulären Rezeptor angiotensin converting Enzyme 2 (ACE2) und vermittelt den viralen Eintritt in Zielzellen. Die Spaltung und Aktivierung des S Proteins durch Wirtszellproteasen ist für den infektiösen, S Protein-vermittelten Zelleintritt von SARS-CoV essentiell. Die Typ II Transmembranserinproteasen (TTSPs) TMPRSS2 und HAT spalten und aktivieren das S Protein, zumindest nach gerichteter Expression in Zelllinien. Ob diese Enzyme in der menschlichen Lunge, den Zielzellen der SARS-CoV-Infektion, exprimiert werden, war jedoch unklar und sollte im Rahmen der vorliegenden Arbeit untersucht werden. TMPRSS2 und HAT spalten auch den viralen Rezeptor ACE2 und es wurde postuliert, dass die ACE2-Spaltung den viralen Eintritt erhöht. Der zugrundeliegende Mechanismus war jedoch nicht bekannt und sollte innerhalb der vorliegenden Arbeit aufgeklärt werden. Es konnte gezeigt werden, dass TMPRSS2 und HAT zusammen mit ACE2 in Epithelzellen des Respirationstrakts exprimiert werden. Die Proteasen könnten daher die Ausbreitung von SARS-CoV im Lungenepithel fördern. Weiterhin wurde eine Aminosäuresequenz in ACE2 identifiziert, die für die Prozessierung durch TMPRSS2 und HAT essentiell ist. Die funktionelle Analyse von ACE2- Mutanten zeigte, dass die Spaltung in diesem Bereich infektionsverstärkend wirkt. Immunfluoreszenz-Studien erbrachten Hinweise darauf, dass die Verstärkung der Infektion auf eine erhöhte Aufnahme von Virus-Partikeln in die Zelle zurückzuführen ist. Schließlich konnte demonstriert werden, dass TMPRSS2 und eine weitere zelluläre Protease, A Disintegrin And Metalloproteinase 17 (ADAM17), um die ACE2-Spaltung konkurrieren und die ADAM17- Spaltstelle in ACE2 konnte kartiert werden. Die ACE2-Spaltung durch ADAM17 war jedoch für den S Protein-getriebenen Zelleintritt verzichtbar. Zusammenfassend zeigen diese Untersuchungen, dass TMPRSS2 und HAT die SARS-CoV-Infektion durch Spaltung von S Protein und Rezeptor fördern. Die Proteasen stellen daher mögliche Angriffspunkte für die antivirale Intervention dar.

In der vorliegenden Arbeit untersuchten wir an einer europäischen Population ausgewählte Polymorphismen zweier Gene auf eine Assoziation zu IA. Beide Gene FIGF und ACE2 sind lokalisiert auf Chromosom Xp22 und stellen damit positionelle Kandidatengene dar, aber auch funktionell sind sie von Interesse, da sie v.a. in Prozesse des Gefäßwachstums (FIGF) und der Blutdruckregulierung (ACE2) involviert sind; Vorgänge also, die möglicherweise in die pathophysiologische Erklärung der IA Entstehung mit hineinspielen. In keinem der insgesamt neun analysierten Polymorphismen konnten wir jedoch eine signifikante Assoziation zu IA finden. Auch eine Analyse möglicher intra- und intergenetischer Haplotypen aller untersuchten Varianten erbrachte kein signifikantes Ergebnis.

In der vorliegenden Arbeit untersuchten wir an einer europäischen Population ausgewählte Polymorphismen zweier Gene auf eine Assoziation zu IA. Beide Gene FIGF und ACE2 sind lokalisiert auf Chromosom Xp22 und stellen damit positionelle Kandidatengene dar, aber auch funktionell sind sie von Interesse, da sie v.a. in Prozesse des Gefäßwachstums (FIGF) und der Blutdruckregulierung (ACE2) involviert sind; Vorgänge also, die möglicherweise in die pathophysiologische Erklärung der IA Entstehung mit hineinspielen. In keinem der insgesamt neun analysierten Polymorphismen konnten wir jedoch eine signifikante Assoziation zu IA finden. Auch eine Analyse möglicher intra- und intergenetischer Haplotypen aller untersuchten Varianten erbrachte kein signifikantes Ergebnis.

Vascular disease is the leading cause of mortality and morbidity in the western world, and account for the 1 of every 3 death’s in the US, but a cure for vascular disease is yet to be realized. Hematopoietic stem progenitor cells (HSPCs) are mobilized from bone marrow and have the innate propensity to accelerate vascular repair by reendothelialization and revascularization of ischemic areas. The vasoreparative ability of HSPCs is largely due to their capacity to home to the areas of hypoxia and their sensitivity to hypoxia plays a critical role in the vasoreparative functions of these cells. The discovery of vasoreparative potential of HSPCs resulted in a breakthrough approach of cell-based therapies for the treatment of ischemic vascular diseases. However, success of this approach is essentially dependent on the number of cells that could be collected from an individual. Therefore, novel mechanism-based strategies are needed to enhance the outcomes of autologous cell-based therapies in poor mobilizers and older adults. Recent evidence of a potential role of the vasoprotective axis of the renin angiotensin system (RAS) in HSPCs functions offers a breakthrough. Angiotensin-(1-7), the primary mediator of the protective functions which acts on Mas receptor (MasR), is generated by angiotensin converting enzyme-2 (ACE2). In this study, we tested the effects of hypoxia on stimulation of vasoreparative potential of HSPCs and in upregulation of ACE2 and MasR. Importantly, we delineated the molecular mechanism of hypoxic exposure in regulation of ACE2 and MasR in a HIF1α- dependent manner and hypoxic exposure induced shedding of the membrane bound ACE2 in HSPCs. We used luciferase, a reporter assay, cell-based assays, gene/protein expression studies and pharmacological strategies in human and mouse HSPCs to test our hypotheses. To verify the biological significance of hypoxia, we performed in vivo studies in mice and humans, which recapitulated the in vitro observations on vascular protective axis of RAS in HSPCs. Collectively, these studies provided mechanistic insights into hypoxic regulation of vascular protective axis of RAS in HSPCs and also provided compelling evidence for the clinical use of hypoxia as a promising approach for enhancing the vasoreparative outcomes of cell-based therapies. / American Heart Association grant, 13SDG16960025 / National Institutes of Health, National institute of Aging (NIA), 1R01AG056881

The angiotensin-converting enzyme 2 (ACE2) receptor has been identified as the entry receptor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that is abundantly expressed in many organs. With respect to the role of circulating ACE2 and its receptor expression in the pathogenesis of the SARS-CoV-2 infection, it is still debated whether diseases such as hypertension or pharmacotherapies, including ACE inhibitors and angiotensin receptor blockers that affect ACE2 receptor expression, may modulate the severity and outcome of the coronavirus disease 2019 (COVID-19). We therefore tested the hypothesis that treatment with the ACE inhibitor Ramipril affects organ-specific ACE2 receptor mRNA and protein expression as well as the serum metabolome in BioBreeding (BB) rats. Twelve male BioBreeding rats were randomly divided into a Ramipril (10 mg/kg body weight) treatment group or a control group (N = 12; n = 6 per group) over a period of seven days. Ramipril treatment resulted in the reduction of acylcarnitines (C3–C6) out of 64 metabolites. Among the different organs studied, only in the lungs did Ramipril treatment significantly increase both Ace2 mRNA and ACE2 receptor membrane protein levels. Increased ACE2 receptor lung expression after Ramipril treatment was not associated with differences in ACE2 serum concentrations between experimental groups. Our data provide experimental in vivo evidence that the ACE inhibitor Ramipril selectively increases pulmonary ACE2 receptor mRNA and protein levels and reduces acylcarnitines.

The prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) quickly reached pandemic proportions, and knowledge about this virus and coronavirus disease 2019 (COVID-19) has expanded rapidly. This review focuses primarily on mechanisms that contribute to acute cardiac injury and dysfunction, which are common in patients with severe disease. The etiology of cardiac injury is multifactorial, and the extent is likely enhanced by pre-existing cardiovascular disease. Disruption of homeostatic mechanisms secondary to pulmonary pathology ranks high on the list, and there is growing evidence that direct infection of cardiac cells can occur. Angiotensin converting enzyme 2 (ACE2) plays a central role in COVID-19 and is a necessary receptor for viral entry into human cells. ACE2 normally not only eliminates angiotensin II (Ang II) by converting it to Ang (1-7), but also elicits a beneficial response profile counteracting that of Ang II. Molecular analyses of single nuclei from human hearts have shown that ACE2 is most highly expressed by pericytes. Given the important roles that pericytes have in the microvasculature, infection of these cells could compromise myocardial supply to meet metabolic demand. Furthermore, ACE2 activity is crucial for opposing adverse effects of locally generated Ang II, so virus-mediated internalization of ACE2 could exacerbate pathology by this mechanism. While the role of cardiac pericytes in acute heart injury by SARS-CoV-2 requires investigation, expression of ACE2 by these cells has broader implications for cardiac pathophysiology.

Angiotensin-converting enzyme 2 (ACE2) has been identified as the cellular entry receptor for the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). High ACE2 tissue expression and low glycine levels were suggested to increase susceptibility for SARS-CoV-2 infection and increasing circulating ACE2 has been proposed as one possible strategy to combat COVID-19. In humans, aerobic physical exercise induces an increase in plasma ACE2 in some individuals. However, it is not clear whether glycine and ACE2 levels depend on intrinsic exercise capacity or on exercise training. We used rats selectively bred for high intrinsic exercise capacity (HCR) or low exercise capacity (LCR) and tested the influence of this genetic predetermination and/or aerobic exercise on metabolites, ACE2 tissue expression and circulating ACE 2. ACE2 expression was measured in different tissues in the sedentary animals and again after 4 weeks of high-intensity aerobic exercise in both LCRs and HCRs. Sedentary HCRs exhibited significantly higher circulating ACE2 concentrations compared to LCRs, but a lower expression of ACE2 in all investigated tissues except for adipose tissue. Body weight was negatively correlated with serum ACE2 and positively correlated with ACE2 expression in the heart. Aerobic exercise caused a significant decrease in ACE2 expression in the lung, heart, muscle, and kidney both in LCRs and HCRs. Our results suggest that ACE2 expression, circulating ACE2 and glycine serum concentration are related to aerobic intrinsic exercise capacity and can be influenced with exercise. These results may support the hypothesis that physically fit individuals have a lower susceptibility for COVID-19 infection.

No description available.