Nitric Oxide Mediates Benefits of Angiotensin II Type 2 Receptor Overexpression During Post-Infarct Remodeling

Abstract

Abstract-We hypothesized that nitric oxide (NO) mediates the benefits of cardiac angiotensin II type 2 (AT 2 -R) overexpression during postmyocardial infarction (post-MI) remodeling. Eleven wild-type (WT) C57BL/6 mice and 28 transgenic (TG) mice with AT 2 -R overexpression were studied by cardiac magnetic resonance imaging (CMR) at baseline and days 1 and 28 post-MI induced by left anterior descending artery occlusion and reperfusion. Sixteen TG mice were treated from day 1 through 28 post-MI with the NO synthase inhibitor N G -nitro-L-arginine methyl ester in drinking water at 1 mg/mL (TG-Rx). Left ventricular mass index (LVMI), end-diastolic volume index (EDVI) and end-systolic volume index (ESVI), wall thickness, percent thickening, and ejection fraction (EF) were measured. Infarct size on day 1 was assessed by post-contrast CMR. Interstitial collagen was quantified in noninfarcted regions. At baseline, heart rate (HR), blood pressure (BP), LVMI, EDVI, and ESVI were similar between groups, as were infarct size and weekly post-MI HR and systolic BP. By day 28 post-MI, EDVI and ESVI were similar in WT and TG-Rx, but significantly lower in TG (ESVI: 1.41Ϯ0.18 L/g versus 2.53Ϯ0.14 L/g in WT; 2.17Ϯ0.14 L/g in TG-Rx; PϽ0.008 for both). At day 28, EF was higher in TG (46.3%Ϯ2.9%) compared with WT and TG-Rx (32.7Ϯ2.3% and 33.7Ϯ2.3, respectively; PϽ0.003 for both). Wall thickening at day 28 post-MI was greater in the base and mid-LV in TG than WT and TG-Rx. Noninfarcted region interstitial collagen was similar between groups. Thus, the NO pathway may mediate much of the benefits of cardiac AT 2 -R overexpression during post-MI remodeling. . 1 However, the role of the angiotensin II type 2 receptor (AT 2 -R) in left ventricular (LV) remodeling in disease states is an area of active investigation. [2][3][4][5][6] In fact, many of the beneficial effects of AT 1 -R blockade postmyocardial infarction (post-MI) or of angiotensin-converting enzyme (ACE) inhibitors may be mediated by Ang II stimulation of the AT 2 -R. 7,8 We have previously demonstrated that AT 2 -R overexpression in the mouse heart preserves LV size and function during post-MI remodeling. 9 The transgenic mice (TG) demonstrated preserved LV cavity size, wall thickness within the infarct zone, and regional and global LV function during post-MI remodeling compared with wild-type controls (WT). Others have shown that deletion of the AT 2 -R is detrimental post-MI, leading to myocardial rupture, 10 heart failure, and increased mortality. 10,11 Studies in vascular smooth muscle and the kidney suggest that the benefits of AT 2 -R stimulation may be through signaling pathways involving the kinin and nitric oxide (NO) system 12 AT 2 -R-mediated increases in cGMP caused by bradykinin and NO have been demonstrated in studies of the aorta and kidney, 13,14 and blood pressure-lowering effects of AT 1 -R blockade involve AT 2 -R-mediated release of renal bradykinin and NO production. 15 Recently, Ang II stimulation of the AT 2 -R in the TG model of cardiac overexpression...

Cardiovascular and Renal Regulation by the Angiotensin Type 2 Receptor

“…This group of investigators has recently extended this study to demonstrate that the cardiac NO pathway is largely, if not exclusively, responsible for the beneficial effects of AT 2 receptor expression. 35 NOS inhibitor L-NAME was able to abrogate virtually all of the protective actions of cardiac AT 2 receptor overexpression after MI LV remodeling. 35 Beneficial effects of cardiac-specific AT 2 receptor overexpression included reduced LV wall thickening, decreased end-diastolicand end-systolic volume indices, and increased ejection fraction after MI compared with WT mice.…”

“…35 NOS inhibitor L-NAME was able to abrogate virtually all of the protective actions of cardiac AT 2 receptor overexpression after MI LV remodeling. 35 Beneficial effects of cardiac-specific AT 2 receptor overexpression included reduced LV wall thickening, decreased end-diastolicand end-systolic volume indices, and increased ejection fraction after MI compared with WT mice. These results are for the most part consonant with the work of Xu et al, 36 who demonstrated that the cardioprotective effects of AT 1 receptor activation are mediated by the AT 2 receptor, even though the AT 2 receptor may not play a role in the regulation of normal (basal) cardiac function.…”

Angiotensin II potentiates adrenergic and muscarinic modulation of guinea pig intracardiac neurons

“…The importance of elevated ANG II levels in cardiac disease is becoming increasingly clear, and studies have shown evidence for negative outcomes associated with increased AT 1 receptor activation (14,21). Conversely, increased activation of AT 2 receptors is associated with cardioprotection (9,10,25). While cardiomyoctes express AT 1 and AT 2 receptors, most of the functional changes (electrical and mechanical) induced by ANG II exposure to the heart in vivo are mediated indirectly via induced alterations in autonomic efferent function (15,20).…”

Angiotensin II type 2 receptor-stimulated activation of plasma prekallikrein and bradykinin release: role of SHP-1

“…Some of the beneficial effects of AT 2 R are mediated by bradykinin/ nitric oxide (NO) (5,10), and overexpression of AT 2 R in the vasculature reportedly stimulated the kinin system, causing dilatation (31). Likewise cardiac AT 2 R overexpression attenuated fibrosis induced by ANG II or myocardial infarction, apparently acting via a kinin/NO-dependent mechanism (3,7). We have demonstrated that the cardioprotective effects of AT 1 R antagonists are mediated in part by activation of AT 2 R and kinins, since they were diminished in AT 2 R or kinin receptors knock out mice and kinin-deficient rats or by blocking the AT 2 R or kinin receptors (11, 34 -36).…”