Transgenic Angiotensin-Converting Enzyme 2 Overexpression in Vessels of SHRSP Rats Reduces Blood Pressure and Improves Endothelial Function

Abstract

Abstract-Rat models of hypertension, eg, spontaneously hypertensive stroke-prone rats (SHRSP), display reduced angiotensin-converting enzyme 2 (ACE2) mRNA and protein expression compared with control animals. The aim of this study was to investigate the role of ACE2 in the pathogenesis of hypertension in these models. Therefore, we generated transgenic rats on a SHRSP genetic background expressing the human ACE2 in vascular smooth muscle cells by the use of the SM22 promoter, called SHRSP-ACE2. In these transgenic rats vascular smooth muscle expression of human ACE2 was confirmed by RNase protection, real-time RT-PCR, and ACE2 activity assays. Transgene expression leads to significantly increased circulating levels of angiotensin-(1-7), a prominent product of ACE2. Mean arterial blood pressure was reduced in SHRSP-ACE2 compared to SHRSP rats, and the vasoconstrictive response to intraarterial administration of angiotensin II was attenuated. The latter effect was abolished by previous administration of an ACE2 inhibitor. To evaluate the endothelial function in vivo, endothelium-dependent and endothelium-independent agents such as acetylcholine and sodium nitroprusside, respectively, were applied to the descending thoracic aorta and blood pressure was monitored. Endothelial function turned out to be significantly improved in SHRSP-ACE2 rats compared to SHRSP. These data demonstrate that vascular ACE2 overexpression in SHRSP reduces hypertension probably by locally degrading angiotensin II and improving endothelial function. Thus, activation of the ACE2/angiotensin-(1-7) axis may be a novel therapeutic strategy in hypertension. (Hypertension. 2008;52:967-973.)

Angiotensin-Converting Enzyme (ACE) 2 Overexpression Ameliorates Glomerular Injury in a Rat Model of Diabetic Nephropathy: A Comparison with ACE Inhibition

“…Recently, the role of ACE2 in the modulation of cardiovascular function has been investigated by deliberate genetic manipulation, including targeted disruption (5,6) and overexpression (7)(8)(9), and these studies have consistently demonstrated that ACE2 has beneficial effects of antihypertension, antifibrosis and antiatherosclerosis. Thus, ACE2 may provide a new therapeutic target for the treatment of cardiovascular diseases.…”

Heat Shock Prevents Insulin Resistance–Induced Vascular Complications by Augmenting Angiotensin-(1-7) Signaling

“…This suggests that enhanced ANG II/AT 1 signaling in the aortas of HFD-fed rats might be responsible for the downregulation of ANG-(1-7)/MAS/ACE2 axis and NO bioavailability. Overexpression of ACE2 or chronic ANG-(1-7) infusion has been shown to reduce blood pressure, and this effect may be due to the degrading of local ANG II and the improving of endothelial dysfunction (46,47). Previously, HS has been shown to suppress ANG II-induced hypertension in aorta (23).…”

Multiple Functions of Angiotensin-Converting Enzyme 2 and Its Relevance in Cardiovascular Diseases

“…7 In another line of ACE2 knockout mice, BP was significantly increased following Ang II infusions, 47 in sharp contrast to the spontaneous hypotension observed in ACE knockout mice, 48 suggesting that, in addition to the Ang II system, ACE2 might regulate BP through other peptide systems, such as bradykinin and/or Apelin. Nevertheless, exogenous supplementation of ACE2 by gene transfer decreased BP in SHR hypertensive rats, 38 and recombinant ACE2 treatment attenuated Ang II-induced hypertension specifically. 49 Thus, ACE2 clearly must function as a negative regulator of the RAS in BP control.…”

“…Those hypertensive rats show reduced ACE2 transcripts and protein expression in both heart and kidney. 7 Transgenic ACE2 overexpression in the vessels of SHRSP rats reduces blood pressure (BP) and improves endothelial function, 38 and neuronal overexpression of ACE2 also attenuates hypertension. 39, 40 In humans, several studies have shown a strong association of ACE2 polymorphisms to hypertension in female Chinese patients with metabolic syndrome, 41 essential hypertension 42-45 or diabetes-associated hypertension.…”