Mitochondrial angiotensin receptors and cardioprotective pathways

Abstract

A growing body of data provides strong evidence that intracellular angiotensin II (ANG II) plays an important role in mammalian cell function and is involved in the pathogenesis of human diseases such as hypertension, diabetes, inflammation, fibrosis, arrhythmias, and kidney disease, among others. Recent studies also suggest that intracellular ANG II exerts protective effects in cells during high extracellular levels of the hormone or during chronic stimulation of the local tissue renin-angiotensin system (RAS). Notably, the intracellular RAS (iRAS) described in neurons, fibroblasts, renal cells, and cardiomyocytes provided new insights into regulatory mechanisms mediated by intracellular ANG II type 1 (AT₁Rs) and 2 (AT₂Rs) receptors, particularly, in mitochondria and nucleus. For instance, ANG II through nuclear AT₁Rs promotes protective mechanisms by stimulating the AT₂R signaling cascade, which involves mitochondrial AT₂Rs and Mas receptors. The stimulation of nuclear ANG II receptors enhances mitochondrial biogenesis through peroxisome proliferator-activated receptor-γ coactivator-1α and increases sirtuins activity, thus protecting the cell against oxidative stress. Recent studies in ANG II-induced preconditioning suggest that plasma membrane AT₂R stimulation exerts protective effects against cardiac ischemia-reperfusion by modulating mitochondrial AT₁R and AT₂R signaling. These studies indicate that iRAS promotes the protection of cells through nuclear AT₁R signaling, which, in turn, promotes AT₂R-dependent processes in mitochondria. Thus, despite abundant data on the deleterious effects of intracellular ANG II, a growing body of studies also supports a protective role for iRAS that could be of relevance to developing new therapeutic strategies. This review summarizes and discusses previous studies on the role of iRAS, particularly emphasizing the protective and counterbalancing actions of iRAS, mitochondrial ANG II receptors, and their implications for organ protection.

Keywords: angiotensin II receptors; cardioprotection; heart; intracellular renin-angiotensin system; mitochondria.

Fig. 1.

Proposed mechanisms of mitochondria-mediated cardioprotection by ANG II-preconditioning (APC). APC operates through plasma membrane ANG II type 1 (AT₁Rs) and 2 (AT₂Rs) receptors that are blocked by losartan and PD123319, respectively. Stimulation of these receptors leads to PKCε activation and translocation of AT₁R, AT₂R, Akt, ERK1/2, JNK, p38, and PKG to the mitochondria where they exert their protective role. AT₁Rs also stimulate NAD(P)H oxidase (NOX) activity leading to superoxide generation, mitoK_ATP channel activity, membrane depolarization, and mitochondrial permeability transition pores (mPTP) opening. This process enhances the efflux of superoxide into the cytoplasm and promotes the activation of prosurvival kinases. By contrast, AT₂R stimulation leads to nitric oxide synthase (NOS)-nitric oxide (NO)-PKG stimulation that further stimulates PKCε. In the mitochondria, the upregulation of AT₂R/AT₁R protein levels controls the respiratory chain activity through a stimulatory mechanism composed of NOX4-reactive oxygen species (ROS) and an inhibitory pathway involving NOS-NO. The latter is proposed to exert a master control on respiratory function as it modulates AT₁Rs while tonically suppressing electron transport chain activity.

Fig. 2.

Main signaling pathways involved in mitochondria-mediated cardioprotection by ischemic preconditioning (IPC). IPC is triggered by ligands (i.e., adenosine, bradykinin, and opioids, among others) that through receptor-mediated processes stimulate signaling pathways involved in cardioprotection. Prosurvival kinases involved in these pathways [phosphatidylinositol 3-kinase (PI3K)-Akt and Ras-Raf-MEK1/2-ERK1/2] are activated and translocated to the mitochondria to exert protective action. Both pathways lead to inhibition of GSK-3β, which blocks the mitochondrial permeability transition pores (mPTP). Also, the activation of the PI3K-Akt signaling mechanism, promote activation of PKCє through the endothelial nitric oxide synthase (eNOS)-nitric oxide (NO)-PKG pathway. Stimulation of mitoK_ATP channel leads to reduced mitochondrial potential and inhibition of mPTP opening. Reactive oxygen species (ROS) generation by stimulation of respiratory chain activity promotes the continuous stimulation of PKCε and cardioprotection.

Fig. 3.

Proposed mechanism of regulation of mitochondrial function by extracellular ANG II receptors. Activation of plasma membrane receptors of ANG II leads to endocytic internalization and trafficking of the ANG II-ANG II type 1 receptor (AT₁R) complex to an intracellular (“processing”) pool that also contains the synthesized AT₁Rs. ANG II from intracellular synthesis binds to translocated AT₁Rs in the nuclear membrane and the mitochondria. At the nucleus, the complex stimulates transcription and synthesis of ANG II type 2 receptors (AT₂Rs) that are also translocated to the mitochondria, the plasma membrane and the nucleus. Nuclear AT₁Rs also lead to the synthesis of intracellular renin-angiotensin system (RAS) components and ANG II generation. The process can also be stimulated by oxidative stress. ANG II receptors localized at the plasma membrane, nucleus, endoplasmic reticulum, and mitochondria regulate cell metabolism through signaling pathways including reactive oxygen species (ROS), nitric oxide (NO), and PKCε-dependent cascades, among others (see Fig. 1). AGT, angiotensinogen.