Sex Hormones Promote Opposite Effects on ACE and ACE2 Activity, Hypertrophy and Cardiac Contractility in Spontaneously Hypertensive Rats

Abstract

BackgroundThere is growing interest in sex differences and RAS components. However, whether gender influences cardiac angiotensin I-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2) activity is still unknown. In the present work, we determined the relationship between ACE and ACE2 activity, left ventricular function and gender in spontaneously hypertensive rats (SHRs).Methodology / Principal FindingsTwelve-week-old female (F) and male (M) SHRs were divided into 2 experimental groups (n = 7 in each group): sham (S) and gonadectomized (G). Fifty days after gonadectomy, we measured positive and negative first derivatives (dP/dt maximum left ventricle (LV) and dP/dt minimum LV, respectively), hypertrophy (morphometric analysis) and ACE and ACE2 catalytic activity (fluorimetrically). Expression of calcium handling proteins was measured by western blot. Male rats exhibited higher cardiac ACE and ACE2 activity as well as hypertrophy compared to female rats. Orchiectomy decreased the activity of these enzymes and hypertrophy, while ovariectomy increased hypertrophy and ACE2, but did not change ACE activity. For cardiac function, the male sham group had a lower +dP/dt than the female sham group. After gonadectomy, the +dP/dt increased in males and reduced in females. The male sham group had a lower -dP/dt than the female group. After gonadectomy, the -dP/dt increased in the male and decreased in the female groups when compared to the sham group. No difference was observed among the groups in SERCA2a protein expression. Gonadectomy increased protein expression of PLB (phospholamban) and the PLB to SERCA2a ratio in female rats, but did not change in male rats.ConclusionOvariectomy leads to increased cardiac hypertrophy, ACE2 activity, PLB expression and PLB to SERCA2a ratio, and worsening of hemodynamic variables, whereas in males the removal of testosterone has the opposite effects on RAS components.

Sex-Specific SARS-CoV-2 Mortality: Among Hormone-Modulated ACE2 Expression, Risk of Venous Thromboembolism and Hypovitaminosis D

“…More in detail, 17ß-estradiol may increase the expression/activity of ACE2 in the adipose tissue and the kidney. As reported above, spontaneously hypertensive male mice showed higher ACE2 expression than female mice [15], which may provide a possible explanation for the higher mortality in men due to more severe cardiovascular damage that the viral infection is capable of causing. Since the expression of ACE2 in the myocardium appears to be modulated by androgen [15], a role for androgen receptor (AR) gene polymorphisms cannot be excluded in the pathogenesis of cardiovascular adverse events and hypertension in COVID-19-positive male patients.…”

“…This caused blood hypertension that was reversed by the administration of losartan [14]. The same authors had previously shown a low expression of ACE2 in the adipose tissue of male mice [15]. In contrast, high-fat-fed female mice have an increased expression of ACE2 in the adipose tissue, which leads to high angiotensin (1-7) levels and no hypertension until angiotensin (1-7) receptor antagonists are administered.…”

“…Indeed, stimulation with human chorionic gonadotropic (hCG) improves the ACE2-angiotensin (1-7)-Mas system [14]. This may represent a compensatory mechanism that could be useful for avoiding an increase in blood pressure in postmenopausal women [15]. In addition to gonadal expression, some studies have shown an expression and activity of ACE2 influenced by sex hormones in the mouse adipose tissue, kidneys and myocardium [15][16][17][18].…”

“…This may represent a compensatory mechanism that could be useful for avoiding an increase in blood pressure in postmenopausal women [15]. In addition to gonadal expression, some studies have shown an expression and activity of ACE2 influenced by sex hormones in the mouse adipose tissue, kidneys and myocardium [15][16][17][18]. Gupte and colleagues studied the contribution of ACE2 in the pathogenesis of the sex-related difference of obesity-related hypertension.…”

“…After orchiectomy, a significant decrease in ACE, ACE2 expression and cardiac hypertrophy was found and, consequently an increased cardiac performance was observed. Finally, ovariectomy causes an increase in ACE2 expression and cardiac hypertrophy, which worsens the function of the heart pump [15].…”