Angiotensin II Type 2 Receptor Antagonizes Angiotensin II Type 1 Receptor–Mediated Cardiomyocyte Autophagy

Abstract

Abstract-Autophagy has emerged as an important process in the pathogenesis of cardiovascular diseases, but the proximal triggers for autophagy are unknown. Angiotensin II plays a central role in the pathogenesis of cardiac hypertrophy and heart failure. In this study, we used angiotensin II type 1 (AT 1 ) and type 2 (AT 2 ) receptor-expressing adenoviruses in cultured neonatal cardiomyocytes to provide the first demonstration that neonatal cardiomyocyte autophagic activity is differentially modulated by AT 1 and AT 2 receptor subtypes. 4 and its function is less well delineated. Normally present only at low levels in the adult myocardium, AT 2 expression is upregulated in the pathological remodeling heart. 3 AT 2 -mediated cardiovascular responses have been characterized as generally opposing AT 1 -mediated growth effects, but some studies indicate that the AT 2 receptor is also involved in inducing left ventricular hypertrophy. 5,6 We have also shown that the AT 2 receptor can mediate myocyte hypertrophy independent of Ang II in isolated neonatal cardiomyocytes. 7 Thus, the role of the AT 2 receptor remains ambiguous.Autophagy is an intracellular degradation process that involves the destruction of long-lived proteins and organelles. Recently, autophagy has been particularly recognized as important in the turnover of cytoplasmic constituents in the heart. Autophagic activity is commonly increased in the heart under conditions that also involve upregulation of the reninangiotensin system. For example, high levels of autophagy are found in the heart after acute and chronic ischemia, heart failure, and neonatal starvation. 8 There is emerging evidence that pressure overload, a major risk factor for cardiac hypertrophy and heart failure, is associated with an excess of autophagy, which is ultimately maladaptive under such conditions of hemodynamic stress. 9 The proximal triggers for autophagy in the heart are not known.AT 1 receptor activation stimulates protein synthesis and protein turnover in cardiomyocytes. Intracellular protein aggregation is an important precursor event for cardiomyocyte autophagy. 10 Thus, links among activation of the renin-angiotensin system, protein turnover stimulation, and autophagic upregulation may be identified in several pathophysiological myocardial conditions. Therefore, in this study we hypothesized that the AT 1 and AT 2 receptor subtypes play a

The Impact of Autophagy on Cardiovascular Senescence and Diseases

“…52) In relation to the renin-angiotensin-aldosterone system, angiotensin II stimulation activates autophagy via the angiotensin II type 1 (AT1) but not angiotensin II type 2 (AT2) receptors in neonatal rat cardiomyocytes. 53,54) Angiotensin II stimulation of AT1 receptors alone activates autophagy, whereas stimulation of AT2 receptors strongly decreases autophagy in a rat model of heart hypertrophy. 53) Thus, an AT1 receptor antagonist may treat heart failure by reducing cell death caused by excessive autophagy.…”

“…53,54) Angiotensin II stimulation of AT1 receptors alone activates autophagy, whereas stimulation of AT2 receptors strongly decreases autophagy in a rat model of heart hypertrophy. 53) Thus, an AT1 receptor antagonist may treat heart failure by reducing cell death caused by excessive autophagy. However, another study suggested that low autophagic flux in cardiac hypertrophy is required to elicit an adaptive response, and complete obstruction of this process generally has extremely negative results.…”

Angiotensin Receptors and Autophagy

“…Presumably, it will not take long until the major findings by Porrello et al, 7 a stimulatory effect on autophagy by the AT 1 R and inhibition of autophagy via the AT 2 R, will be validated by other groups. Confirmation of these data will be important in particular in experiments using primary (not genetically altered) cells, because artificially modified receptor expression levels may have an impact on receptor heterodimerization or other receptor-protein interactions resulting in altered receptor signaling.…”

“…The main achievement of the article by Porrello et al 7 published in this issue of Hypertension is that it bridges the gap between the 2 biological systems of RAS and autophagy and provides first evidence for an interplay between these 2 systems in cardiomyocytes. Porrello et al 7 report that neonatal rat cardiomyocytes overexpressing either the AT 1 R or the AT 2 R or both after adenoviral transfection present with either an augmented (via the AT 1 R) or inhibited (via the AT 2 R) autophagic response on stimulation by angiotensin II (Figure). Their finding is based on the determination of the number of autophagosomes labeled by fluorescent HcRed microtubule-associated protein 1 light chain 3.…”

DNA methylation and chromatin dynamics during postnatal cardiomyocyte maturation

“…qPCR was performed on the StepOnePlus™ Real-Time PCR System (Thermo Fisher Scientific (Applied Biosystems)) using SYBR® Green PCR Master Mix (Thermo Fisher Scientific (Invitrogen)), as previously described (Porrello et al, 2009). Standard PCR primers for qPCR are listed in Table 2.1, 2.2.…”