8.4  Role of n-3 PUFAs in modulating the renin-angiotensin aldosterone system in the setting of COVID-19
The renin-angiotensin aldosterone system (RAAS) is a key regulator of vascular function modulating natriuresis, blood volume and blood pressure. Briefly, angiotensin I (Ang I) is metabolized by angiotensin-converting enzyme (ACE) to form the vasoconstrictor angiotensin II (Ang II). Accumulation, prolonged and excessive binding of Ang II to the angiotensin 1 receptor in the heart and blood vessels mediates several effects which include vasoconstriction, hypertension, cardiac hypertrophy, increased ROS production and adverse fibrosis (Fyhrquist, Metsarinne, & Tikkanen, 1995; Perazella & Setaro, 2003). Earlier literature demonstrated Ang II may act as a proinflammatory cytokine potentially having a significant role in cardiac remodeling (Gibbons, Pratt, & Dzau, 1992; Griendling, Minieri, Ollerenshaw, & Alexander, 1994). Conversely, the master regulator ACE2, a type 1 integral membrane glycoprotein expressed in most tissues including the lungs, kidneys, heart and vascular endothelium layers, can metabolize Ang II to produce the vasodilator angiotensin (Ang 1–7) which protects the cardiovascular system against the actions of Ang II (Das, 2018; Kumar & Das, 1997; Yan et al., 2020). Beside its vasodilatory properties, Ang-(1–7) promotes resolution of inflammation by decreasing TNF-α, IL-6, vascular adhesion molecule, monocyte chemoattractant protein-1 and macrophage infiltration enhancing the survival of cardiomyocytes and endothelial cells during severe immune responses (Simoes e Silva, Silveira, Ferreira, & Teixeira, 2013; Zhang et al., 2015). Accordingly, several clinical and experimental studies reported dysregulation of RAAS due to increased Ang II and decreased ACE2 can lead to detrimental inflammatory responses and worsening of cardiovascular disorders. Therefore, maintaining the activity of ACE2 is essential in preserving the balance of the RAAS and effects on vasoconstriction, sodium retention and fibrosis and may elicit protective effects against hypertension, HF, MI and other CVDs (Crackower et al., 2002; Patel et al., 2016; Wang, Gheblawi, & Oudit, 2020).
Recent evidence has demonstrated SARS-CoV-2 uses ACE2 as an internalization receptor to enter the target cells. The spike (S) glycoprotein of SARS-CoV-2 recognizes and interacts with its target ACE2 receptor on the host cell surface, mediating viral entry during the infection cycle (Letko, Marzi, & Munster, 2020; Yan et al., 2020). Excessive binding of spike protein to ACE2 leads to downregulation of the ACE2 receptor (Jung et al., 2020). This finding is consistent with reports in the animal models infected with SARS-CoV (Crackower et al., 2002; Imai et al., 2005; Kuba et al., 2005). The reduction in ACE2 levels leads to excessive pro-inflammatory responses adversely affecting both lung and cardiovascular systems (Crackower et al., 2002; Imai et al., 2005; Kuba et al., 2005). These detrimental effects can be explained as the partial decrease in ACE2 function leads to dominant angiotensin II effects, including augmented cytokine storm, inflammation, vasoconstriction and susceptibility for thrombosis. These effects further increase the cardiovascular burden by worsening hypertension, HF and other cardiovascular disorders in predisposed patients (Liu, Blet, Smyth, & Li, 2020; Oudit et al., 2009). Importantly, the accumulation of Ang II was positively associated to viral load and lung injury (Liu et al., 2020). Moreover, reduction in the activity and/or number of ACE2 leads to deficiency of Ang-(1–7) production and consequently loss of its anti-inflammatory, vasodilatory, and cardiovascular protective effects (Lelis, Freitas, Machado, Crespo, & Santos, 2019; Patel et al., 2016). Therefore, it is hypothesized that inhibition of RAAS may be helpful to attenuate the inflammatory storm and ameliorate end-organ damage. Interestingly, recent data indicates individuals with COVID-19 who are being treated with ACE inhibitors or ARBs, for pre-existing conditions, are at lower risk of 28-day all-cause mortality than those not treated with ACE inhibitors or ARBs (Wang et al., 2020; Zhang et al., 2020). Although ARBs and ACE inhibitors do not directly impact ACE2, they indirectly elevate ACE2 activity and the beneficial Ang-(1–7) production and counter the excessive production of the harmful Ang II (Hanff, Harhay, Brown, Cohen, & Mohareb, 2020). Therefore, it was proposed that maintaining the levels of ACE2 and its downstream effector Ang-(1–7) may limit cardiovascular damage secondary to COVID-19 (Wang, Edin, et al., 2020).
Interestingly, several reports showed that n-3 PUFAs can regulate the RAAS system by modulating both Ang II and ACE2 levels. For instance, emerging literature indicates n-3 PUFAs and their endogenously generated metabolites can directly reduce the expression and activity of ACE, thereby reducing angiotensin II formation and cardiovascular burden (Kumar & Das, 1997). Moreover, it has been demonstrated that supplementation of mice with an n-3 PUFA rich diet for three weeks resulted in attenuated Ang-II-induced blood pressure via up-regulation of ACE2 (Ulu et al., 2013). Alternatively, as previously discussed, incorporation of n-3 PUFAs into the cell membranes will alter key properties, which can consequently affect protein number and affinity of SARS-CoV-2 to ACE2 (Candelario & Chachisvilis, 2013; Das, 1999, Das, 2020b; Glende et al., 2008). Together, these studies suggest a novel role for n-3 PUFAs in regulating SARS-CoV-2 infection where the potential benefit as an adjuvant therapy involves increasing the production of Ang-(1–7) and reducing the levels of Ang II, thereby limiting COVID-19-triggered cardiovascular complications.
Importantly, evidence demonstrating upregulation and enhanced activity of ACE2 suggested it will facilitate the infectivity of SARS-CoV-2 (South, Diz, & Chappell, 2020). Accordingly, some researchers proposed that ACE inhibitors and ARBs should be discontinued in COVID-19 patients (Diaz, 2020; Esler & Esler, 2020). However, in addition to the direct effects on cardiac ACE2 other mechanisms such as triggering a cytokine storm will markedly contribute to SARS-CoV-2-induced injury (Chen, Li, Chen, Feng, & Xiong, 2020). A recent study conducted by Yang et al., demonstrated COVID-19 patients with hypertension using ACE inhibitors/ARBs had lower mortality rates than hypertensive COVID-19 patients that were not on ACE inhibitors/ARBs (Yang et al., 2020). Moreover, Mancia et al. examined 6272 patients and found no association between RAAS inhibitor use and susceptibility or development of COVID-19 (Mancia, Rea, Ludergnani, Apolone, & Corrao, 2020). In that sense, a published statement by American Heart Association (AHA), the American College of Cardiology (ACC) and the Heart Failure Society of America strongly recommended continuation of ACE inhibitor/ARBs (Zhang, Zhu, Cai, et al., 2020). Together, these data suggest therapies targeting ACE and Ang II do not appear to increase the likelihood of SARS-CoV-2 infection, but may have a role in abrogating the inflammatory response and vasoconstriction that contributes to the clinical deterioration in COVID-19 patients.
In summary, evidence has demonstrated infection with SARS-CoV-2 induces internalization and downregulation of ACE2, which may aggravate a patient's condition by limiting the degradation of Ang II. Elevated Ang II levels induce several detrimental effects on the cardiovascular system including elevated blood pressure, excessive recruitment and infiltration of inflammatory immune cells to the heart as well as increased secretion of pro-inflammatory cytokines. Reduced ACE2 levels are associated with decreased formation of Ang-(1–7) and thus loss of its vasodilatory, anti-inflammatory and CVD-protective effects. Therefore, intervention with treatments to correct an imbalance in the RAAS system, such as ACE inhibitors, ARBs and n-3 PUFAs, can possibly improve the outcomes.