4.3 Cardiovascular system impairment in COVID-19
Patients with COVID-19 may have higher risk to develop complications and progress into severe cases when having coronal heart disease(Huanget al. , 2020). Among the hospitalized patients infected SARS-CoV-2, acute cardiac injury is one of the common complications. The cardiac injury found in COVID-19 patients may be at least partially attributed to the fluctuation of ACE2 expression. Former researches have proved that elevated cardiac and plasma Ang Ⅱ levels were correlated with the heart contractility impairment after deletion of ACE2(Gurleyet al. , 2006; Yamamoto et al. , 2006). It was found that ACE2 has the potential possibility to remodel and regulate heart function because ACE2 knockout mice has severe cardiac dysfunction(Nakamura et al. , 2008). Knockout mice of ACE genes or treatment with AT1 receptor blockers reversed the cardiac phenotype in ACE2 knockout mice(Oudit et al. , 2007). Similarly, the age-dependent cardiomyopathy in ACE2 knockout mice is likely mediated by Ang Ⅱ-induced oxidative stress and inflammation through AT1 receptor by PI3K signaling. Meanwhile, the correlation between the activity of ACE2 in serum and the deterioration of heart failure has been confirmed(Goulter et al. , 2004). Especially, in the development from hypertension to heart failure, the decrease of serum of ACE2 activity suggested a selective biomarker of cardiac systolic dysfunction(Pan et al. , 2018). Further in vivo murine studies showed Ang Ⅱ mediated loss of membrane-bound cardiomyocyte ACE2 correlated with the upregulation of TACE/ADAM 17 activity which was prevented by AT1 receptor blockade(Weber et al. , 1991). Cardiac fibroblasts and coronary endothelial cells also express ACE2 and TACE and this reciprocal relationship extends to these cell types as well(Mehta et al. , 2007). In addition to counterbalancing Ang Ⅱ/AT1R axis, the involvement of Ang (1-7) in the action of ACE2 on regulating heart function has been demonstrated. It is reported that the ACE2/Ang (1-7)/MasR axis plays an importance role in the regulation of RAAS system(Patel et al. , 2016). Treatment with Ang (1-7) peptide has been shown to improve myocardial performance, cardiac remodeling, and even survival in rodent heart failure models(Abwainy et al. , 2016; Santos et al. , 2004). All these evidences have proved that the ACE2/Ang (1-7)/MasR axis plays a very important role in cardiovascular system. Consequently, the impairment of cardiac function in COVID-19 patients is related to the down-regulation of ACE2/Ang (1-7)/MasR axis, which implicates the rebalance of RAAS in the treatment of COVID-19 with cardiovascular system impairment.