The mechanism of low-level arsenic exposure-induced hypertension: Inhibition of the activity of the angiotensin-converting enzyme 2

Abstract

It is now well-established that arsenic exposure induces hypertension in humans. Although arsenic-induced hypertension is reported in many epidemiological studies, the underlying molecular mechanism of arsenic-induced hypertension is not fully characterized. In the human body, blood pressure is primarily regulated by a well-known physiological system known as the renin-angiotensin system (RAS). Hence, we explored the potential molecular mechanisms of arsenic-induced hypertension by investigating the regulatory roles of the RAS. Adult C57BL/6JJcl male mice were divided into four groups according to the concentration of arsenic in drinking water (0, 8, 80, and 800 ppb) provided for 8 weeks. Arsenic significantly raised blood pressure in arsenic-exposed mice compared to the control group, and significantly raised plasma MDA and Ang II and reduced Ang (1–7) levels. RT-PCR results showed that arsenic significantly downregulated ACE2 and MasR in mice aortas. In vitro studies of endothelial HUVEC cells treated with arsenic showed increased level of MDA and Ang II and lower levels of Ang (1–7), compared with the control. Arsenic significantly downregulated ACE2 and MasR expression, as well as those of Sp1 and SIRT1; transcriptional activators of ACE2, in HUVECs. Arsenic also upregulated markers of endothelial dysfunction (MCP-1, ICAM-1) and inflammatory cytokines (IL-6, TNF-α) in HUVECs. Our findings suggest that arsenic-induced hypertension is mediated, at least in part, by oxidative stress-mediated inhibition of ACE2 as well as by suppressing the vasoprotective axes of RAS, in addition to the activation of the classical axis.