Primary and Secondary Signaling Pathways in Early Preconditioning That Converge on the Mitochondria to Produce Cardioprotection

Abstract

Cardioprotective mechanisms such as acute or early preconditioning activate several primary signaling pathways that seem to converge on mitochondrial targets, leading to altered cell metabolism and inhibition of apoptosis. Acute preconditioning leads to generation of agonists, which bind to G protein–coupled receptors, and initiates a signaling cascade that involves activation of phosphoinositide-3-kinase, endothelial NO synthase, protein kinase C, glycogen synthase kinase 3β, mitogen-activated protein kinases, and other signaling pathways. Activation of these signaling pathways along with generation of reactive oxygen species leads to alterations in the activity of key mitochondrial proteins such as mitochondrial ATP-sensitive K⁺ channels, the mitochondrial permeability transition pore, and bcl-2 family members. Alterations in these mitochondrial proteins results in altered metabolism and inhibition of cell death, thus resulting in cardioprotection.