New perspectives on angiotensin-converting enzyme 2 and its related diseases

Table 4 List of epidemiological studies on the role of angiotensin-converting enzyme 2 in diabetes, hypertension, cardiovascular disease, and acute lung injury

Disease	Source country	Patients	Main findings	Ref.
Diabetes	Canada	Renal biopsies from 13 diabetic and 8 control patients	ACE2 mRNA and protein expression were significantly reduced in both the glomeruli and proximal tubules of the diabetic patients	Reich et al[53]
	Japan	66 nondiabetic and 8 diabetic patients with biopsy-proven renal diseases	ACE2 mRNA expression was not significantly changed in the diabetic patients	Konoshita et al[54]
	China	275 Uygur T2D patients and 272 nondiabetic Uygur individuals	ACE2 SNPs rs1978124, rs2048683, rs2074192, rs233575, rs4240157, rs4646156, rs4646188, and rs879922 were associated with T2D	Liu et al[55]
Hypertension	Australia	503 Caucasian subjects with type 2 diabetes	Genetic variation in ACE2 was associated with hypertension and reduced systolic function in men, and hypertension and increased LV mass in women	Patel et al[65]
	China	275 Uygur T2D patients and 272 nondiabetic Uygur individuals	ACE2 SNPs rs2048683, rs233575, rs4240157, rs4646156, rs4646188, and rs879922 were associated with increased SBP, while rs2074192, rs4646188, and rs879922 were associated elevated DBP	Liu et al[55]
	China	402 hypertensive patients and 233 normotensive individuals	ACE2 variant rs2074192 was associated with EH, while rs4240157, rs4646155, and rs4830542 were associated with EH- and hypertension-related atrial fibrillation and left atrial remodeling	Luo et al[66]
	China	3408 untreated hypertensive patients	The T allele of ACE2 rs2106809 was found to confer a 1.6-fold risk for hypertension in women	Fan et al[67]
	China	96 patients with EH and 96 healthy controls	Aberrant methylation of the ACE2 promoter may be associated with EH risk	Fan et al[68]
Cardiovascular disease	United States	11 individuals with dilated cardiomyopathy, 15 individuals with hypertrophic cardiomyopathy, and 16 controls with nonfailing hearts from the Penn Human Heart Tissue Biobank	ACE2 expression was downregulated in fibroblasts, pericytes, and vascular smooth muscle but upregulated in cardiomyocytes in dilated cardiomyopathy and hypertrophic cardiomyopathy	Fan et al[67]
	Hungary	45 healthy individuals, 239 hypertensiveindividuals,141 patients with heart failure (HF) and reduced ejection fraction (HFrEF), and 47 patients with HF and preserved ejection fraction (HFpEF)	ACE2 activity was further increased in HFrEF patients. Serum ACE2 activity was negatively correlated with left ventricular systolic function in HFrEF	Úri et al[74]
	United States	113 patients with chronic systolic heart failure	Elevated plasma soluble ACE2 (sACE2) activity was associated with greater severity of myocardial dysfunction and was an independent predictor of adverse clinical events	Epelman et al[75]
	14 countries across five continents	10753 Prospective Urban Rural Epidemiology participants	Increased concentration of plasma ACE2 was associated with a higher risk of incident heart failure, myocardial infarction, stroke, and diabetes	Narula et al[76]
	Italy	Healthy subjects (C) and EH and Bartter's/Gitelman's (BS/GS) patients	ACE2 was significantly elevated in BS/GS compared with either C or EH	Calò et al[77]
	China	275 Uygur T2D patients and 272 nondiabetic Uygur individuals	ACE2 SNPs rs2074192 and rs879922 were associated with carotid arteriosclerosis stenosis and ACE2 SNPs rs2048683, rs4240157, rs4646156, rs4646188, and rs879922 were linked to heavier left heart remodeling	Liu et al[55]
Acute lung injury	United States	44 patients with acute respiratory distress syndrome (ARDS)	GSK2586881, a rhACE2, was well-tolerated in patients with ARDS, and has been found to reduce Ang II levels and increase Ang 1-7 levels	Khan et al[94]

T2D: type 2 diabetes; EH: Essential hypertension; ACE2: Angiotensin-converting enzyme 2; ARDS: Acute respiratory distress syndrome; SNP: Single nucleotide polymorphism; HF: Heart failure; HFrEF: Heart failure and reduced ejection fraction; HFpEF: Heart failure and preserved ejection fraction; Ang 1-7: Angiotensin 1-7.