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Background Since its discovery in December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected more than 2 180 000 people worldwide and has caused more than 150 000 deaths as of April 16, 2020. SARS-CoV-2, which is the virus causing coronavirus disease 2019 (COVID-19), uses the angiotensin-converting enzyme 2 (ACE2) as a cell receptor to invade human cells. Thus, ACE2 is the key to understanding the mechanism of SARS-CoV-2 infection. This study is to investigate the ACE2 expression in various human tissues in order to provide insights into the mechanism of SARS-CoV-2 infection. Methods We compared ACE2 expression levels across 31 normal human tissues between males and females and between younger (ages ≤ 49 years) and older (ages > 49 years) persons using two-sided Student’s t test. We also investigated the correlations between ACE2 expression and immune signatures in various tissues using Pearson’s correlation test. Results ACE2 expression levels were the highest in the small intestine, testis, kidneys, heart, thyroid, and adipose tissue, and were the lowest in the blood, spleen, bone marrow, brain, blood vessels, and muscle. ACE2 showed medium expression levels in the lungs, colon, liver, bladder, and adrenal gland. ACE2 was not differentially expressed between males and females or between younger and older persons in any tissue. In the skin, digestive system, brain, and blood vessels, ACE2 expression levels were positively associated with immune signatures in both males and females. In the thyroid and lungs, ACE2 expression levels were positively and negatively associated with immune signatures in males and females, respectively, and in the lungs they had a positive and a negative correlation in the older and younger groups, respectively. Conclusions Our data indicate that SARS-CoV-2 may infect other tissues aside from the lungs and infect persons with different sexes, ages, and races equally. The different host immune responses to SARS-CoV-2 infection may partially explain why males and females, young and old persons infected with this virus have markedly distinct disease severity. This study provides new insights into the role of ACE2 in the SARS-CoV-2 pandemic.

Poly(ADP-ribosyl)ation is an immediate cellular repair response to DNA damage and is catalyzed primarily by poly(ADP-ribose)polymerase-1 (PARP1), which is the most abundant of the 18 different PARP isoforms and accounts for more than 90% of the catalytic activity of PARP in the cell nucleus. Upon detection of a DNA strand break, PARP1 binds to the DNA, cleaves nicotinamide adenine dinucleotide between nicotinamide and ribose and then modifies the DNA nuclear acceptor proteins by formation of a bond between the protein and the ADP-ribose residue. This generates ribosyl–ribosyl linkages that act as a signal for other DNA-repairing enzymes and DNA base repair. Extensive DNA breakage in cells results in excessive activation of PARP with resultant depletion of the cellular stores of nicotinamide adenine dinucleotide (NAD+) which slows the rate of glycolysis, mitochondrial electron transport, and ultimately ATP formation in these cells. This paper focuses on PARP in DNA repair in atherosclerosis, acute myocardial infarction/reperfusion injury, and congestive heart failure and the role of PARP inhibitors in combating the effects of excessive PARP activation in these diseases. Free oxygen radicals and nitrogen radicals in arteries contribute to disruption of the vascular endothelial glycocalyx, which increase the permeability of the endothelium to inflammatory cells and also low-density lipoproteins and the accumulation of lipid in the vascular intima. Mild inflammation and DNA damage within vascular cells promote PARP1 activation and DNA repair. Moderate DNA damage induces caspase-dependent PARP cleavage and vascular cell apoptosis. Severe DNA damage due to vascular inflammation causes excessive activation of PARP1. This causes endothelial cell depletion of NAD+ and ATP, downregulation of atheroprotective SIRT1, necrotic cell death, and ultimately atherosclerotic plaque disruption. Inhibition of PARP decreases vascular endothelial cell adhesion P-selectin and ICAM-1 molecules, inflammatory cells, pro-death caspase-3, and c-Jun N-terminal kinase (JNK) activation and upregulates prosurvival extracellular signal-regulated kinases and AKT, which decrease vascular cell apoptosis and necrosis and limit atherosclerosis and plaque disruption. In myocardial infarction with coronary occlusion then reperfusion, which occurs with coronary angioplasty or thrombolytic therapy, reperfusion injury occurs in as many as 31% of patients and is caused by inflammatory cells, free oxygen and nitrogen radicals, the rapid transcriptional activation of inflammatory cytokines, and the activation of PARP1. Inhibition of PARP attenuates neutrophil infiltration and inflammatory cytokine expression in the reperfused myocardium and preserves myocardial NAD+ and ATP. In addition, PARP inhibition increases the activation of myocyte survival enzymes protein kinase B (Akt) and protein kinase C epsilon (PKCε), and decreases the activity of myocardial ventricular remodeling enzymes PKCα/β, PKCζ/λ, and PKCδ. As a consequence, cardiomyocyte and vascular endothelial cell necrosis is decreased and myocardial contractility is preserved. In heart failure and circulatory shock in animal models, PARP inhibition significantly attenuates decreases in left ventricular systolic pressure, ventricular contractility and relaxation, stroke volume, and increases survival by limiting or preventing upregulation of adhesion molecules, proinflammatory cytokines, myocardial mononuclear cell infiltration, and PKCα/β and PKC λ/ζ. In this manner, PARP inhibition partially restores the myocardial concentrations of NAD+, limits ventricular remodeling and fibrosis, and prevents significant decreases in myocardial contractility. Based primarily on investigations in preclinical models of atherosclerosis, myocardial infarction, and heart failure, PARP inhibition appears to be beneficial in limiting or inhibiting cardiovascular dysfunction. These studies indicate that investigations of acute and chronic PARP inhibition are warranted in patients with atherosclerotic coronary artery disease.

Lysine acetylation is a conserved, reversible, post-translational protein modification regulated by lysine acetyltransferases (KATs) and lysine deacetylases (KDACs; also known as histone deacetylases (HDACs)) that is involved in many cellular signalling pathways and diseases. Studies in animal models have revealed a regulatory role of reversible lysine acetylation in hypertension, vascular diseases, arrhythmia, heart failure and angiogenesis. Evidence from these studies indicates a therapeutic role of KDAC inhibitors (also known as HDAC inhibitors) in cardiovascular diseases. In this Review, we describe the diverse roles of KATs and KDACs in both the normal and the diseased heart. Among KDACs, class II and class III HDACs seem to have a protective role against both cardiac damage and vessel injury, whereas class I HDACs protect against vessel injury but have deleterious effects on the heart. These observations have important implications for the clinical utility of HDAC inhibitors as therapeutic agents for cardiovascular diseases. In addition, we summarize the latest data on nonacetylation acylations in the context of cardiovascular disease.Lysine acetyltransferases (KATs) and lysine deacetylases (KDACs) are involved in the regulation of lysine acetylation, a conserved post-translational protein modification that is an important modulator of cardiac metabolism. Li and colleagues describe the complex roles of KATs and KDACs in both the normal and diseased heart and provide an overview of the evidence indicating a therapeutic role of KDAC inhibitors in cardiovascular disease.

Angiotensin-converting enzyme 2 (ACE2) is a new component of the renin-angiotensin system (RAS). Accumulating evidence shows that ACE2 provides protective effects in peripheral tissues and has great potential for the treatment of RAS-related diseases. The role of ACE2 in the central nervous system is not well established. However, in recent years, much more progress has been made on the studies of this carboxypeptidase in the central regulation of blood pressure and cardiovascular function in general. It has been shown that brain ACE2 interacts with the other components of the RAS (ACE, angiotensin II, and angiotensin II type 1 receptor), protects baroreflex and autonomic function, stimulates nitric oxide release, reduces oxidative stress, and prevents the development of or attenuates hypertension. These data support the critical role of ACE2 in the central regulation of cardiovascular function. This review summarizes recently published data on the central effects of ACE2 in the regulation of cardiovascular function.

Adenosine Monophosphate-activated Protein Kinase （AMPK）, a serine/threonine kinase and a member of the Snfl/AMPK protein kinase family, consists of three protein subunits that together make a functional enzyme. AMPK, which is expressed in a number of tissues, including the liver, brain, and skeletal muscle, is allosterically activated by a rise in the AMP： ATP ratio （ie in a low ATP or energy depleted state）. The net effect of AMPK activation is to halt energy consuming （anabolic） pathways but to promote energy conserving （catabolic） cellular pathways. AMPK has therefore often been dubbed the ＂metabolic master switch＂. AMPK also plays a critical physiological role in the cardiovascular system, increasing evidence suggest that AMPK might also function as a sensor by responding to oxidative stress. Mostly importantly, AMPK modulates endogenous antioxidant gene expression and/or suppress the production of oxidants. AMPK promotes cardiovascular homeostasis by ensuring an optimum redox balance on the heart and vascular tissues. Dysfunctional AMPK is thought to underlie several cardiovascular pathologies. Here we review this kinase from its structure and discovery to current knowledge of its adaptive and maladaptive role in the cardiovascular system.

All eukaryotic cells contain the phospholipid phosphatidylinositol 4, 5-bisphosphate (PIP₂) that serves multiple roles in signal transduction cascades. Type I phosphatidylinositol-4-phosphate 5-kinase (PIP5KI) catalyzes the synthesis of PIP₂ by phosphorylating phosphatidylinositol 4 phosphate. Although the classical isoforms of PIP5KI (designated as α, β, and γ) all generate the same phospholipid product, they have significantly dissimilar primary structures and expression levels in different tissues, and they appear to localize within different compartments within the cell. Therefore, it appears likely that PIP5KI isoforms have overlapping, but not identical, functions. Here we show that targeted disruption of PIP5KIγ causes widespread developmental and cellular defects. PIP5KIγ-null embryos have myocardial developmental defects associated with impaired intracellular junctions that lead to heart failure and extensive prenatal lethality at embryonic day 11.5 of development. Loss of PIP5KIγ also results in neural tube closure defects that were associated with impaired PIP₂ production, adhesion junction formation, and neuronal cell migration. These data, along with those of other PIP5KI isoforms, indicate that individual PIP5KI isoenzymes fulfill specific roles in embryonic development.

The N-end rule relates the in vivo half-life of a protein to the identity of its N-terminal residue. A subset of degradation signals recognized by the N-end rule pathway comprises the signals, called N-degrons, whose determinants include destabilizing N-terminal residues. Our previous work identified a family of at least four mammalian E3 ubiquitin ligases, including UBR1 and UBR2, that share the UBR box and recognize N-degrons. These E3 enzymes mediate the multifunctional N-end rule pathway, but their individual roles are just beginning to emerge. Mutations of UBR1 in humans are the cause of Johanson-Blizzard syndrome. UBR1 and UBR2 are 46% identical and appear to be indistinguishable in their recognition of N-degrons.$UBR1^{-/-}$mice are viable but have defects that include pancreatic insufficiency, similarly to$UBR1^{-/-}$human patients with Johanson-Blizzard syndrome.$UBR2^{-/-}$mice are inviable in some strain backgrounds and are defective in male meiosis. To examine functional relationships between UBR1 and UBR2, we constructed mouse strains lacking both of these E3s. We report here that$UBR1^{-/-}UBR2^{-/-}$embryos die at midgestation, with defects in neurogenesis and cardiovascular development. These defects included reduced proliferation as well as precocious migration and differentiation of neural progenitor cells. The expression of regulators such as D-type cyclins and Notch1 was also altered in$UBR1^{-/-}UBR2^{-/-}$embryos. We conclude that the functions of UBR1 and UBR2 are significantly divergent, in part because of differences in their expression patterns and possibly also because of differences in their recognition of protein substrates that contain degradation signals other than N-degrons.

[...]gamma-glutamyl transpeptidase/transferase (GGT) levels and FRS are positively correlated among non-diabetic, non-obese adults. [...]adding GGT to conventional CVR factors is unlikely to improve the prediction of first-ever cardiovascular events in the general population [23] . [...]a large cross-sectional study found no significant association of GGT concentration with carotid intima media thickness or plaques [24] . (iii) What is the evidence for a link between GGT and NAFLD? Loomba et al[28] performed a phenotypic study in 362 twins and concluded that the beta2-adrenergic receptor gene had pleiotropic effects on plasma levels of GGT and triglycerides, indicating linked adrenergic pathways between the genetic susceptibility to develop both NAFLD and the metabolic syndrome. [...]genetic and metabolic influences modulate the risk of developing elevated GGT values in NAFLD. (iv) How should CVR be diagnosed and managed in those with fatty liver? Given that, in NAFLD patients, cardiovascular (rather than liver-related) events are the leading cause of morbidity and mortality, NAFLD is increasingly recognized as an independent CVR factor [2],[8] . [...]in the future, properly designed and conducted studies need to ascertain whether adding NAFLD will result - as expected - in the currently used risk scores, e.g. the FRS, predicting cardiovascular events more accurately [9] .

It has recently been demonstrated that purified NAD(P)H:quinone oxidoreductase 1 (NQO1) is able to scavenge superoxide (O2(.-)) though the rate of reaction of O2(.-) with NQO1 is much lower than the rate of enzymatic dismutation catalyzed by superoxide dismutase (SOD). This study was undertaken to determine if the endogenously expressed NQO1 in cardiovascular cells could scavenge O2(.-). We observed that NQO1 was highly expressed in cardiovascular cells, including rat aortic smooth muscle A10 and cardiac H9c2 cells, as well as normal human aortic smooth muscle and endothelial cells. NQO1, but not SOD in the cardiovascular cells was highly inducible by 3H-1,2-dithiole-3-thione (D3T). Cytosols from H9c2 and human aortic smooth muscle cells (HASMCs) were isolated to determine the O2(.-) scavenging ability of the endogenously expressed NQO1 by using pyrogallol autooxidation assay. We showed that cytosols from the above cells inhibited pyrogallol autooxidation in an NADPH or NADH-dependent manner. The NADH/NADPH-dependent inhibition of pyrogallol autooxidation by the cytosols was completely abolished by the NQO1-specific inhibitor, ES936, suggesting that the endogenously expressed NQO1 could scavenge O2(.-). In the presence of NADH/NADPH, cytosols from D3T-treated cells showed increased ability to scavenge O2(.-) as compared to cytosols from untreated cells. This increased ability to scavenge O2(.-) was also completely reversed by ES936. 5-(Diethoxyphosphoryl)-5-methyl-1-pyrroline-N-oxide spin-trapping experiments using potassium superoxide as a O2(.-) generator further confirmed the ability of NQO1 from HASMCs to scavenge O2(.-). The spin-trapping experiments also showed that induction of NQO1 by D3T in HASMCs augmented the O2(.-) scavenging ability. Taken together, these results demonstrate that the highly expressed and inducible endogenous NQO1 in cardiovascular cells may act as a potential O2(.-) scavenger.

Hypertensive cardiac disease is a major cause of death worldwide. Causative factors of hypertension include environmental stressors, genetic predisposition, and common morbidities of lipid metabolism such as obesity and diabetes. These factors pathologically elevate the systemic production of vasoconstrictive G-protein-coupled receptor agonists. Pathological concentrations of these agonists upregulate the gene expression and proteolytic activity of matrix metalloproteinases (MMPs) and A disintegrin and metalloproteinases (ADAMs). Among the metalloproteinases that act in concert with other mediators to elevate the systemic blood pressure and to modulate the development of cardiovascular hypertrophy and fibrosis processes are MMP-2, MMP-7, ADAM-12, and ADAM-17. This review offers insights into the activity, differential expression, mutual regulation, and functions of these metalloproteinases. We further review evidence linking them to transcription factors, carrier proteins, and receptors for lipids. The emerging links between metalloproteinases and lipids are intriguing and suggest new therapeutic targets in hypertensive cardiac disease.