Role of the ACE2/Angiotensin 1-7 Axis of the Renin-Angiotensin System in Heart Failure

Heart failure (HF) remains the most common cause of death and disability, and a major economic burden, in industrialized nations. Physiological, pharmacological, and clinical studies have demonstrated that activation of the renin-angiotensin system is a key mediator of HF progression. Angiotensin-converting enzyme 2 (ACE2), a homolog of ACE, is a monocarboxypeptidase that converts angiotensin II into angiotensin 1-7 (Ang 1-7) which, by virtue of its actions on the Mas receptor, opposes the molecular and cellular effects of angiotensin II. ACE2 is widely expressed in cardiomyocytes, cardiofibroblasts, and coronary endothelial cells. Recent preclinical translational studies confirmed a critical counter-regulatory role of ACE2/Ang 1-7 axis on the activated renin-angiotensin system that results in HF with preserved ejection fraction. Although loss of ACE2 enhances susceptibility to HF, increasing ACE2 level prevents and reverses the HF phenotype. ACE2 and Ang 1-7 have emerged as a key protective pathway against HF with reduced and preserved ejection fraction. Recombinant human ACE2 has been tested in phase I and II clinical trials without adverse effects while lowering and increasing plasma angiotensin II and Ang 1-7 levels, respectively. This review discusses the transcriptional and post-transcriptional regulation of ACE2 and the role of the ACE2/Ang 1-7 axis in cardiac physiology and in the pathophysiology of HF. The pharmacological and therapeutic potential of enhancing ACE2/Ang 1-7 action as a novel therapy for HF is highlighted

Targeting the ACE2 and Apelin Pathways Are Novel Therapies for Heart Failure: Opportunities and Challenges

Angiotensin-converting enzyme 2 (ACE2)/Ang II/Ang 1–7 and the apelin/APJ are two important peptide systems which exert diverse effects on the cardiovascular system. ACE2 is a key negative regulator of the renin-angiotensin system (RAS) where it metabolizes angiotensin (Ang) II into Ang 1–7, an endogenous antagonist of Ang II. Both the prolonged activation of RAS and the loss of ACE2 can be detrimental as they lead to functional deterioration of the heart and progression of cardiac, renal, and vascular diseases. Recombinant human ACE2 in an animal model of ACE2 knockout mice lowers Ang II. These interactions neutralize the pressor and subpressor pathologic effects of Ang II by producing Ang 1–7 levels in vivo, that might be cardiovascular protective. ACE2 hydrolyzes apelin to Ang II and, therefore, is responsible for the degradation of both peptides. Apelin has emerged as a promising peptide biomarker of heart failure. The serum level of apelin in cardiovascular diseases tends to be decreased. Apelin is recognized as an imperative controller of systemic blood pressure and myocardium contractility. Dysregulation of the apelin/APJ system may be involved in the predisposition to cardiovascular diseases, and enhancing apelin action may have important therapeutic effects

Pharmacological and cell-specific genetic PI3Kα inhibition worsens cardiac remodeling after myocardial infarction

BACKGROUND: PI3Kα (Phosphoinositide 3-kinase α) regulates multiple downstream signaling pathways controlling cell survival, growth, and proliferation and is an attractive therapeutic target in cancer and obesity. The clinically-approved PI3Kα inhibitor, BYL719, is in further clinical trials for cancer and overgrowth syndrome. However, the potential impact of PI3Kα inhibition on the heart and following myocardial infarction (MI) is unclear. We aim to determine whether PI3Kα inhibition affects cardiac physiology and post-MI remodeling and to elucidate the underlying molecular mechanisms. METHODS AND RESULTS: Wildtype (WT) 12-wk old male mice receiving BYL719 (daily, p.o.) for 10 days showed reduction in left ventricular longitudinal strain with normal ejection fraction, weight loss, mild cardiac atrophy, body composition alteration, and prolonged QTC interval. RNASeq analysis showed gene expression changes in multiple pathways including extracellular matrix remodeling and signaling complexes. After MI, both p110α and phospho-Akt protein levels were increased in human and mouse hearts. Pharmacological PI3Kα inhibition aggravated cardiac dysfunction and resulted in adverse post-MI remodeling, with increased apoptosis, elevated inflammation, suppressed hypertrophy, decreased coronary blood vessel density, and inhibited Akt/GSK3β/eNOS signaling. Selective genetic ablation of PI3Kα in endothelial cells was associated with worsened post-MI cardiac function and reduced coronary blood vessel density. In vitro, BYL719 suppressed Akt/eNOS activation, cell viability, proliferation, and angiogenic sprouting in coronary and human umbilical vein endothelial cells. Cardiomyocyte-specific genetic PI3Kα ablation resulted in mild cardiac systolic dysfunction at baseline. After MI, cardiac function markedly deteriorated with increased mortality concordant with greater apoptosis and reduced hypertrophy. In isolated adult mouse cardiomyocytes, BYL719 decreased hypoxia-associated activation of Akt/GSK3β signaling and cell survival. CONCLUSIONS: PI3Kα is required for cell survival (endothelial cells and cardiomyocytes) hypertrophic response, and angiogenesis to maintain cardiac function after MI. Therefore, PI3Kα inhibition that is used as anti-cancer treatment, can be cardiotoxic, especially after MI

Adeno-Associated Virus Overexpression of Angiotensin-Converting Enzyme-2 Reverses Diabetic Retinopathy in Type 1 Diabetes in Mice

Angiotensin-converting enzyme (ACE)-2 is the primary enzyme of the vasoprotective axis of the renin angiotensin system that regulates the classic renin angiotensin system axis. We aimed to determine whether local retinal overexpression of adenoassociated virus (AAV)-ACE2 prevents or reverses diabetic retinopathy. Green fluorescent protein (GFP)-chimeric mice were generated to distinguish resident (retinal) from infiltrating bone marrow-derived inflammatory cells and were made diabetic using streptozotocin injections. Retinal digestion using trypsin was performed and acellular capillaries enumerated. Capillary occlusion by GFP(+) cells was used to measure leukostasis. Overexpression of ACE2 prevented (prevention cohort: untreated diabetic, 11.3 ± 1.4; ACE2 diabetic, 6.4 ± 0.9 per mm(2)) and partially reversed (reversal cohort: untreated diabetic, 15.7 ± 1.9; ACE2 diabetic, 6.5 ± 1.2 per mm(2)) the diabetes-associated increase of acellular capillaries and the increase of infiltrating inflammatory cells into the retina (F4/80(+)) (prevention cohort: untreated diabetic, 24.2 ± 6.7; ACE2 diabetic, 2.5 ± 1.6 per mm(2); reversal cohort: untreated diabetic, 56.8 ± 5.2; ACE2 diabetic, 5.6 ± 2.3 per mm(2)). In both study cohorts, intracapillary bone marrow-derived cells, indicative of leukostasis, were only observed in diabetic animals receiving control AAV injections. These results indicate that diabetic retinopathy, and possibly other diabetic microvascular complications, can be prevented and reversed by locally restoring the balance between the classic and vasoprotective renin angiotensin system

Endothelial and cardiomyocyte PI3Kβ divergently regulate cardiac remodelling in response to ischaemic injury

AIMS: Cardiac remodeling in the ischemic heart determines prognosis in patients with ischemic heart disease (IHD), while enhancement of angiogenesis and cell survival has shown great potential for IHD despite translational challenges. Phosphoinositide 3-kinase (PI3K)/Akt signaling pathway plays a critical role in promoting angiogenesis and cell survival. However, the effect of PI3Kβ in the ischemic heart is poorly understood. This study investigates the role of endothelial and cardiomyocyte PI3Kβ in post-infarct cardiac remodeling. METHODS AND RESEARCH: PI3Kβ catalytic subunit-p110β level was increased in infarcted murine and human hearts. Using cell type-specific loss-of-function approaches, we reported novel and distinct actions of p110β in endothelial cells versus cardiomyocytes in response to myocardial ischemic injury. Inactivation of endothelial p110β resulted in marked resistance to infarction and adverse cardiac remodeling with decreased mortality, improved systolic function, preserved microvasculature, and enhanced Akt activation. Cultured endothelial cells with p110β knockout or inhibition displayed preferential PI3Kα/Akt/eNOS signaling that consequently promoted protective signaling and angiogenesis. In contrast, mice with cardiomyocyte p110β-deficiency exhibited adverse post-infarct ventricular remodeling with larger infarct size and deteriorated cardiac function, which was due to enhanced susceptibility of cardiomyocytes to ischemia-mediated cell death. Disruption of cardiomyocyte p110β signaling compromised nuclear p110β and phospho-Akt levels leading to perturbed gene expression and elevated pro-cell death protein levels, increasing the susceptibility to cardiomyocyte death. A similar divergent response of PI3Kβ endothelial and cardiomyocyte mutant mice was seen using a model of myocardial ischemia-reperfusion injury. CONCLUSIONS: These data demonstrate novel, differential, and cell-specific functions of PI3Kβ in the ischemic heart. While loss of endothelial PI3Kβ activity produces cardioprotective effects, cardiomyocyte PI3Kβ is protective against myocardial ischemic injury

Cardiac-Specific Elevations in Thyroid Hormone Enhance Contractility and Prevent Pressure Overload-Induced Cardiac Dysfunction

Thyroid hormone (TH) is critical for cardiac development and heart function. In heart disease, TH metabolism is abnormal, and many biochemical and functional alterations mirror hypothyroidism. Although TH therapy has been advocated for treating heart disease, a clear benefit of TH has yet to be established, possibly because of peripheral actions of TH. To assess the potential efficacy of TH in treating heart disease, type 2 deiodinase (D2), which converts the prohormone thyroxine to active triiodothyronine (T3), was expressed transiently in mouse hearts by using the tetracycline transactivator system. Increased cardiac D2 activity led to elevated cardiac T3 levels and to enhanced myocardial contractility, accompanied by increased Ca(2+) transients and sarcoplasmic reticulum (SR) Ca(2+) uptake. These phenotypic changes were associated with up-regulation of sarco(endo)plasmic reticulum calcium ATPase (SERCA) 2a expression as well as decreased Na(+)/Ca(2+) exchanger, beta-myosin heavy chain, and sarcolipin (SLN) expression. In pressure overload, targeted increases in D2 activity could not block hypertrophy but could completely prevent impaired contractility and SR Ca(2+) cycling as well as altered expression patterns of SERCA2a, SLN, and other markers of pathological hypertrophy. Our results establish that elevated D2 activity in the heart increases T3 levels and enhances cardiac contractile function while preventing deterioration of cardiac function and altered gene expression after pressure overload

SARS-CoV-2 Infections and ACE2: Clinical Outcomes Linked With Increased Morbidity and Mortality in Individuals With Diabetes

Individuals with diabetes suffering from coronavirus disease 2019 (COVID-19) exhibit increased morbidity and mortality compared with individuals without diabetes. In this Perspective, we critically evaluate and argue that this is due to a dysregulated renin-angiotensin system (RAS). Previously, we have shown that loss of angiotensin-I converting enzyme 2 (ACE2) promotes the ACE/angiotensin-II (Ang-II)/angiotensin type 1 receptor (AT1R) axis, a deleterious arm of RAS, unleashing its detrimental effects in diabetes. As suggested by the recent reports regarding the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), upon entry into the host, this virus binds to the extracellular domain of ACE2 in nasal, lung, and gut epithelial cells through its spike glycoprotein subunit S1. We put forth the hypothesis that during this process, reduced ACE2 could result in clinical deterioration in COVID-19 patients with diabetes via aggravating Ang-II–dependent pathways and partly driving not only lung but also bone marrow and gastrointestinal pathology. In addition to systemic RAS, the pathophysiological response of the local RAS within the intestinal epithelium involves mechanisms distinct from that of RAS in the lung; however, both lung and gut are impacted by diabetes-induced bone marrow dysfunction. Careful targeting of the systemic and tissue RAS may optimize clinical outcomes in subjects with diabetes infected with SARS-CoV-2.This study was supported by National Institutes of Health grants R01EY025383, R01EY012601, R01EY028858, and R01EY028037 to M.B.G. A.G.O. was supported in part by R01NS10241

ACE2 Deficiency Worsens Epicardial Adipose Tissue Inflammation and Cardiac Dysfunction in Response to Diet-Induced Obesity

Obesity is increasing in prevalence and is strongly associated with metabolic and cardiovascular disorders. The renin-angiotensin system (RAS) has emerged as a key pathogenic mechanism for these disorders; angiotensin (Ang)-converting enzyme 2 (ACE2) negatively regulates RAS by metabolizing Ang II into Ang 1-7. We studied the role of ACE2 in obesity-mediated cardiac dysfunction. ACE2 null (ACE2KO) and wild-type (WT) mice were fed a high-fat diet (HFD) or a control diet and studied at 6 months of age. Loss of ACE2 resulted in decreased weight gain but increased glucose intolerance, epicardial adipose tissue (EAT) inflammation, and polarization of macrophages into a proinflammatory phenotype in response to HFD. Similarly, human EAT in patients with obesity and heart failure displayed a proinflammatory macrophage phenotype. Exacerbated EAT inflammation in ACE2KO-HFD mice was associated with decreased myocardial adiponectin, decreased phosphorylation of AMPK, increased cardiac steatosis and lipotoxicity, and myocardial insulin resistance, which worsened heart function. Ang 1-7 (24 µg/kg/h) administered to ACE2KO-HFD mice resulted in ameliorated EAT inflammation and reduced cardiac steatosis and lipotoxicity, resulting in normalization of heart failure. In conclusion, ACE2 plays a novel role in heart disease associated with obesity wherein ACE2 negatively regulates obesity-induced EAT inflammation and cardiac insulin resistance