Roles of the nitric oxide signaling pathway in cardiac ischemic preconditioning against myocardial ischemia-reperfusion injury

Abstract

Nitric oxide (NO), a vasoactive gas that can freely diffuse into the cell, has many physiological effects in various cell types. Since 1986, numerous studies of ischemic preconditioning against ischemia-reperfusion (I/R) injury have been undertaken and the roles of the NO signaling pathway in cardioprotection have been explored. Many studies have confirmed the effect of NO and that its relative signaling pathway is important for preconditioning of the cardioprotective effect. The NO signaling against I/R injury targeted on the mitochondria is believed to be the end-target for cardioprotection. If the NO signaling pathway is disrupted or inhibited, cardioprotection by preconditioning disappears. During preconditioning, signaling is initiated from the sarcolemmal membrane, and then spread into the cytoplasm via many series of enzymes, including nitric oxide synthase (NOS), the NO-producing enzyme, soluble guanylyl cyclase (sGC), and protein kinase G (PKG). Finally, the signal is transmitted into the mitochondria, where the cardioprotective effect occurs. It is now well established that mitochondria act to protect the heart against I/R injury via the opening of the mitochondrial ATP-sensitive K+ channel and the inhibition of mitochondrial permeability transition (MPT). This knowledge may be useful in developing novel strategies for clinical cardioprotection from I/R injury.

Figure 1

The schematic diagram represents the ischemic preconditioning pathway in cardiomyocytes. IPC induces cardiomyocytes to release adenosine, bradykinin and endogenous opioid which occupy their specific G-protein coupled receptors. After that, the signal will pass into the cytosol via the activation of the enzyme series including PI3K, PDKs, Akt and NOS. The latter enzyme produces NO which acts as signaling molecule to activate sGC and resulted in the cGMP formation. Then, cGMP activates PKG which has the separated mechanism on the mitochondria, the direct and indirect mechanism. The direct mechanism of PKG is on the R1 protein on outer mitochondrial membrane which then activates the opening of mitoK_ATP channel on the inner mitochondrial membrane via the phosphorylation of PKCε1. The indirect mechanism of PKG is the phosphorylation of ERK and GSK3β which then act on mitoK_ATP channel. However, the mechanism of how GSK3β activates the opening of mitoK_ATP channel is still unclear. After the mitoK_ATP channel opening, K⁺ then enters the mitochondrial matrix and H⁺ is ejected out of the matrix to balance the positive charge. When H⁺ level decreases, the electron transport chain is interrupted and leads to the formation of superoxide anion and then H₂O₂. Finally, H₂O₂ will act as signaling molecule to activate PKCε2 which then inhibits the opening of mitochondrial permeable transition pore (mPTP). This inhibition of mPTP opening helps to protect mitochondrial damage during I/R injury. (Modified with permission from [63]).