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

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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.

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Funding

This study was supported by the National Institutes of Health Research Centers in Minority Institutions (RCMI) Program grant G12M007600, National Institute of General Medical Sciences grant SC1GM128210 (S.J.), and the University of Puerto Rico.

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  1. Department of Physiology, University of Puerto Rico School of Medicine, PO BOX 365067, San Juan, 00936-5067, Puerto Rico

    Rebeca E. Nuñez, Sabzali Javadov & Nelson Escobales

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Nuñez, R.E., Javadov, S. & Escobales, N. Critical role of angiotensin II type 2 receptors in the control of mitochondrial and cardiac function in angiotensin II-preconditioned rat hearts. Pflugers Arch - Eur J Physiol 470, 1391–1403 (2018). https://doi.org/10.1007/s00424-018-2153-9

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