Cardiac-specific overexpression of angiotensin II AT2 receptor causes attenuated response to AT1 receptor-mediated pressor and chronotropic effects.

Abstract

Angiotensin (Ang) II has two major receptor isoforms, AT1 and AT2. Currently, AT1 antagonists are undergoing clinical trials in patients with cardiovascular diseases. Treatment with AT1 antagonists causes elevation of plasma Ang II which selectively binds to AT2 and exerts as yet undefined effects. Cardiac AT2 level is low in adult hearts, whereas its distribution ratio is increased during cardiac remodeling and its action is enhanced by application of AT1 antagonists. Although in AT2 knock-out mice sensitivity to the pressor action of Ang II was increased, underlying mechanisms remain undefined. Here, we report the unexpected finding that cardiac-specific overexpression of the AT2 gene using alpha-myosin heavy chain promoter resulted in decreased sensitivity to AT1-mediated pressor and chronotropic actions. AT2 protein undetectable in the hearts of wild-type mice was overexpressed in atria and ventricles of the AT2 transgenic (TG) mice and the proportions of AT2 relative to AT1 were 41% in atria and 45% in ventricles. No obvious morphological change was observed in the myocardium and there was no significant difference in cardiac development or heart to body weight ratio between wild-type and TG mice. Infusion of Ang II to AT2 TG mice caused a significantly attenuated increase in blood pressure response and the change was completely blocked by pretreatment with AT2 antagonist. This decreased sensitivity to Ang II-induced pressor action was mainly due to the AT2-mediated strong negative chronotropic effect and exerted by circulating Ang II in a physiological range that did not stimulate catecholamine release. Isolated hearts of AT2 transgenic mice perfused using a Langendorff apparatus also showed decreased chronotropic responses to Ang II with no effects on left ventricular dp/dt max values, and Ang II-induced activity of mitogen-activated protein kinase was inhibited in left ventricles in the transgenic mice. Although transient outward K+ current recorded in cardiomyocytes from AT2 TG mice was not influenced by AT2 activation, this study suggested that overexpression of AT2 decreases the sensitivity of pacemaker cells to Ang II. Our results demonstrate that stimulation of cardia AT2 exerts a novel antipressor action by inhibiting AT1-mediated chronotropic effects, and that application of AT1 antagonists to patients with cardiovascular diseases has beneficial pharmacotherapeutic effects of stimulating cardiac AT2.

Angiotensin Type 2 Receptor Signaling in Satellite Cells Potentiates Skeletal Muscle Regeneration

“…AT2R expression then rapidly declines in newborn animals to low or undetectable levels. Interestingly, AT2R expression in the adult reappears under pathophysiological conditions such as vascular injury and cardiac remodeling (39,40). In some tissues, such as vascular smooth muscle, the AT2R is reported to mediate effects counterbalancing those mediated by the AT1R, e.g.…”

Expression of angiotensin type II receptor downregulates Cdk4 synthesis and inhibits cell-cycle progression

“…In contrast to these findings, we did not observe any significant proapoptotic effect of the AT 2 receptor in exponentially proliferating or serum-starved Rat1 fibroblasts. Similarly, no apoptotic changes were observed in cardiac myocytes from transgenic mice overexpressing the AT 2 receptor in the heart (Masaki et al, 1998). These observations suggest that the proapoptotic effect of the AT 2 receptor may be celltype specific.…”

“…Different exposure times are shown in order to detect Cdk4 in all the conditions tested. Immunoblots were quantified by densitometric analysis and the mean half-lives were calculated from three different experiments Huang et al, 1996;Yamada et al, 1996;Bedecs et al, 1997), and in the heart of transgenic mice overexpressing the AT 2 receptor (Masaki et al, 1998). However, it is unlikely that inhibition of the ERK mitogen-activated protein kinase pathway is responsible for the antiproliferative action of the AT 2 receptor, at least in rat fibroblasts.…”

Angiotensin II and the Heart

“…39,40 Studies in transgenic animals have shed further light on the importance of AT 1A and AT 2 receptors in cardiac function, growth, and remodeling. [41][42][43][44] AT 1A receptor knockout mice display less left ventricular remodeling and greater survival after myocardial infarction. 43 Disruption of the mouse AT 2 receptor gene resulted in a significant increase in blood pressure, 42 whereas cardiac-specific overexpression of AT 2 receptors in mice attenuated the AT 1 receptor-mediated pressor and chronotropic effects.…”

“…43 Disruption of the mouse AT 2 receptor gene resulted in a significant increase in blood pressure, 42 whereas cardiac-specific overexpression of AT 2 receptors in mice attenuated the AT 1 receptor-mediated pressor and chronotropic effects. 44 Furthermore, in humans, the AT 1 receptor A/C 1166 polymorphism and the A/G 1675 gene variant of the AT 2 receptor modulate left ventricular hypertrophy. 45,46 In summary, activation of cell-surface AT 1 receptors is responsible for most of the Ang II-mediated effects in the heart, specifically those on growth and remodeling, and some of these effects are counteracted by AT 2 receptor activation.…”