Critical role of angiotensin II type 2 receptors in the control of mitochondrial and cardiac function in angiotensin II-preconditioned rat hearts

Abstract

Angiotensin II preconditioning (APC) involves an angiotensin II type 1 receptor (AT1-R)-dependent translocation of PKCε and survival kinases to the mitochondria leading to cardioprotection after ischemia-reperfusion (IR). However, the role that mitochondrial AT1-Rs and angiotensin II type 2 receptors (AT2-Rs) play in APC is unknown. We investigated whether pretreatment of Langendorff-perfused rat hearts with losartan (L, AT1-R blocker), PD 123,319 (PD, AT2-R blocker), or their combination (L + PD) affects mitochondrial AT1-R, AT2-R, PKCε, PKCδ, Akt, PKG-1, MAPKs (ERK1/2, JNK, p38), mitochondrial respiration, cardiac function, and infarct size (IS). The results indicate that expression of mitochondrial AT1-Rs and AT2-Rs were enhanced by APC 1.91-fold and 2.32-fold, respectively. Expression of AT2-R was abolished by PD but not by L, whereas the AT1-R levels were abrogated by both blockers. The AT1-R response profile to L and PD was also shared by PKCε, Akt, MAPKs, and PKG-1, but not by PKCδ. A marked increase in state 3 (1.84-fold) and respiratory control index (1.86-fold) of mitochondria was observed with PD regardless of L treatment. PD also enhanced the post-ischemic recovery of rate pressure product (RPP) by 74% (p< 0.05) compared with APC alone. Losartan, however, inhibited the (RPP) by 44% (p < 0.05) before IR and reduced the APC-induced increase of post-ischemic cardiac recovery by 73% (p < 0.05). Finally, L enhanced the reduction of IS by APC through a PD-sensitive mechanism. These findings suggest that APC upregulates angiotensin II receptors in mitochondria and that AT2-Rs are cardioprotective through their permissive action on AT1-R signaling and the suppression of cardiac function.

Mitochondrial angiotensin receptors and cardioprotective pathways

“…These data agree with previous results (51) indicating that blockade of AT 2 R with PD123319 prevented the cardioprotection against I/R injury in valsartan-treated hearts. Altogether, these studies (66 -68) demonstrate that during APC, extracellular ANG II affects mitochondrial function through AT 2 R signaling, protecting the heart and reducing infarct size in the course of I/R injury (68). Therefore, these findings are consistent with and extend previous reports (1,98) on functional ANG II receptors in isolated mitochondria from various cell preparations.…”

“…These effects of APC and losartan were prevented by PD123319. However, ARBs did not affect hearts without APC (68). These observations indicate that AT 2 R activity in APC is responsible for the beneficial effects of the AT 1 R blockade on infarct size.…”

“…Most importantly, inhibition of AT 2 R with PD123319 induced a marked stimulation of mitochondrial (state 3) respiration that was observed even after losartan treatment (68). The stimulatory effect of the AT 2 R antagonist resulted in a pronounced increase in respiratory control index indicating the activation of the respiratory chain and ATP production.…”

The intracellular renin-angiotensin system: Friend or foe. Some light from the dopaminergic neurons

“…A number of recent data support this protective view ( Nunez et al, 2014 , 2017 , 2018 ; Wanka et al, 2020 ; Wilson et al, 2016 ). Several studies have also shown that high levels of intracellular Ang II led to cell and tissue damage ( Redding et al, 2010 ; Singh et al, 2008 ).…”

Mitochondrial dysfunction in cardiovascular disease: Current status of translational research/clinical and therapeutic implications

“…Extracellular Ang II influences mitochondrial function via AT2-R signaling, protecting the myocardium and decreasing infarct size in the course of I/R injury. 46…”