Renin-Angiotensin System overactivation in polycystic ovary syndrome, a risk for SARS-CoV-2 infection?

Abstract

Background: The SARS-CoV-2 coronavirus gains entry to target cells via the angiotensin-converting enzyme 2 (ACE2) receptor present on cells in blood vessels, lungs, heart, intestines, and kidneys. Renin-Angiotensin System (RAS) overactivity has also been described in metabolic syndrome, type 2 diabetes (T2D) and obesity, conditions shared by women with polycystic ovary syndrome (PCOS) We hypothesized that RAS overactivity may be present in PCOS.

Methods: We determined plasma levels of RAS-related proteins in a cohort of age matched control women (n = 97) and women with PCOS (n = 146). Plasma levels of RAS-related proteins (ACE2, Renin and Angiotensinogen (AGT)) were determined by Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement.

Results: PCOS women had a higher BMI (p < 0.001), systolic (p < 0.0001) and diastolic (p < 0.05) blood pressure, waist circumference (p < 0.0001), testosterone (p < 0.0001), free androgen index (p < 0.0001) and CRP (p < 0.0001). Renin was elevated in PCOS (p < 0.05) and angiotensinogen was lower in PCOS (p < 0.05), indicating overactivity of the RAS system in PCOS. ACE2 levels were lower in PCOS (p < 0.05), suggesting that PCOS women are at risk for development of hypertension.

Conclusion: RAS proteins levels differed between PCOS and control women, suggesting that the insulin resistance inherent in PCOS may predispose these women to more severe COVID-19 infection.

Keywords: ACE2 protein; Angiotensinogen; Polycystic ovary syndrome; Renin.

Fig. 1

RAS proteins in women with and without polycystic ovary syndrome (PCOS). Levels of plasma Renin (A), Angiotensinogen (B) and ACE2 (C) in women with and without polycystic ovary syndrome (PCOS). RFU, relative fluorescent units. ∗p < 0.05.

Fig. 2

Schematic diagram of proposed mechanism of COVID-19 severity in women with polycystic ovary syndrome (PCOS). Left panel, in health, under normal physiological conditions (basal state), angiotensinogen is converted into angiotensin I (Ang I) by the hormone/enzyme renin. Ang I is further converted into angiotensin II (Ang II) with the help of the enzyme angiotensin converting enzyme (ACE). Ang II binds to its receptors, angiotensin receptor 1 (AT1R) or angiotensin converting enzyme 2 (ACE2), in different cell surfaces. At basal state, when the Ang II level is low in lung pneumocytes, the catalytic site of the AT1R is occupied with ACE2; therefore, Ang II cannot interact with AT1R and it is then hydrolyzed by ACE2 into angiotensin (1–7) [Ang- (1–7)]. Ang-(1–7) has a cardioprotective effect as it is a potent vasodilator and reduces inflammation. In lung, Ang-(1–7) binds to the Mas receptor (MasR) and protects lung pneumocytes from pulmonary fibrosis. ACE2 serves as the receptor for SARS-CoV-2 and, with the help of a serine protease TMPRSS2, it infects the lung pneumocytes. Since the Ang II level is low in basal conditions, ACE2 remains attached to AT1R and, therefore, there is less access for SARS-CoV-2 to bind to its receptors, resulting in less severe impact in COVID-19. Right panel, in polycystic ovary syndrome (PCOS) women, the plasma renin level is high and the RAS is overactivated, leading to the production of high amounts of Ang II. Excess Ang II causes the dissociation of ACE2 from AT1R and binds to AT1R. Binding of Ang II to AT1R results in vasoconstriction, increased vascular permeability, pulmonary edema and ARDS. When ACE2 becomes detached from AT1R (indicated by broken red arrow), it increases the entry point for SARS-CoV-2 into lung pneumocytes. The viral infection might also be facilitated by overexpression of androgen-induced expression of TMPRSS2 in PCOS, as the androgen levels are higher in PCOS. Upon binding with ACE2, the SARS-CoV-2 -ACE2 complex becomes internalized and undergoes proteasomal degradation of ACE2 inside the cell. This may also cause the reduction of ACE2 levels in lung cells. High Ang II levels also stimulates the adrenal gland to increase aldosterone level which, in turn, decreases potassium and increases sodium levels, and ultimately causes increased blood pressure. Taken together, all these mechanisms could result in a severe outcome for COVID-19-infected women with PCOS. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)