Upregulation of Angiotensin-Converting Enzyme 2 by All- trans Retinoic Acid in Spontaneously Hypertensive Rats

Abstract

Abstract-There is increasing evidence that all-trans retinoic acid (atRA) influences gene expression of components of renin-angiotensin system (RAS), which plays a pivotal role in the pathophysiology of essential hypertension. To further validate effects of atRA on the RAS and to assess the possibility that atRA affects the activity of angiotensin-converting enzyme 2 (ACE2), gene, and protein expression of ACE2 have been examined by real-time polymerase chain reaction and Western blot methods in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. Rats were treated with atRA (10 or 20 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) or placebo given as daily intraperitoneal injection for 1 month. ACE2 expression was markedly decreased in placebo-treated SHR when compared with WKY rats. However, in atRA-treated SHR, a significant upregulation of ACE2 expression was observed in heart and kidney. In conclusion, chronic atRA treatment increases gene and protein expressions of ACE2, resulting in the reduction of blood pressure and the attenuation of myocardial damage in SHR, which suggests that atRA may be an attractive candidate for the potential prevention and treatment of human essential hypertension. Key Words:hypertension, essential Ⅲ angiotensin-converting enzyme Ⅲ renin-angiotensin system Ⅲ rats I t is well-recognized that essential hypertension is a genetically complex metabolic and cardiovascular disorder controlled by both genetic and environmental factors. 1 The ideal aim of modern antihypertensive therapy is not only a reduction of blood pressure but also the prevention or amelioration of its complications, such as myocardial remodeling at the molecular genetic level. 2,3 Research advances on the key transcription factors and nuclear hormone receptors provide insight into the development of novel transcriptionmodulating antihypertensive drugs, among which is all-trans retinoic acid (atRA), a biologically active metabolite of vitamin A. 2 atRA modulates gene transcription and exerts its other effects by binding the retinoic acid receptor (RAR) and retinoid X receptor (RXR) 4,5 and interfering with some key transcription factors such as the activated protein-1. 6,7 Studies have demonstrated that atRA influences the activities of genes responsible for the pathogenesis of hypertension and its complications. 2,3,6,8 Dechow et al 6 reported that atRA reduced blood pressure in the renal damage model. Spontaneously hypertensive rats (SHR) are recognized as genetically hypertensive rats, which resemble, in many aspects, humans with essential hypertension. 9 Chronic atRA treatment prevented medial thickening of intramyocardial and intrarenal arteries and ventricular fibrosis in SHR. 3 However, whether atRA reduces arterial pressure and attenuates myocardial damage in SHR deserves further study.atRA has been shown to regulate the gene expression of components of renin-angiotensin system (RAS), including renin, angiotensin-converting enzyme (ACE), angiotensin (Ang) II, and its type 1 (AT 1 ) receptor. 6,7,10 RAS is critically inv...

Effect of all-trans retinoic acid treatment on prohibitin and renin–angiotensin–aldosterone system expression in hypoxia-induced renal tubular epithelial cell injury

“…These results are in concordance with our previous study, in which we found that ATRA treatment was associated with reduced expression of ACE1 and increased expression of ACE2 in glomerulosclerosis rats. 7 Furthermore, Zhong et al 23 reported that chronic ATRA treatment increased both gene and protein expression of ACE2, which resulted in the reduction of blood pressure and the attenuation of myocardial damage in spontaneously hypertensive rats. ATRA was associated with up-regulated expression of ACE2, and their results and conclusion were similar to ours, albeit in a different cell type.…”

Angiotensin-Converting Enzyme and Angiotensin-Converting Enzyme 2 Are Involved in Sinoaortic Denervation-Induced Cardiovascular Hypertrophy in Rats

“…The result is not consistent with the previous reported that heart ACE2 mRNA and protein expressions were markedly decreased in spontaneously hypertensive rats when compared with WKY rats. 41) However, Gallagher et al showed that myocyte treatment with inhibitors of myocyte and cardiac fibroblast growth, such as Ang-(1-7) or atrial natriuretic peptide reversed the ACE2 mRNA downregulation by hypertrophic hormones like Ang II or ET-1, indicated that ACE2 expression in the heart was dependent upon the regulation and concentration of multiple hypertrophic and anti-hypertropic peptides. 42) Thus the discrepancy may due to the different induced factor of cardiac hypertrophy; high BP in previous study and high BPV in the present study.…”

Ontogeny of angiotensin-converting enzyme 2

“…In addition, ACE2 expression can be induced by retinoic acid (vitamin A). Functionally, induction of ACE2 expression by retinoic acid is associated with reduction in blood pressure in spontaneously hypertensive rats (31).…”