Salvaging the Ischemic Heart: Gi-Coupled Receptors in Mast Cells Activate a PKCε/ALDH2 Pathway Providing Anti-RAS Cardioprotection.

ABSTRACT

BACKGROUND: Excessive norepinephrine (NE) release in the ischemic heart elicits severe and often lethal arrhythmias. Resident cardiac mast cells synthesize and store active renin, which is released upon degranulation, causing the activation of a local cardiac renin-angiotensin system (RAS) responsible for NE release and consequent arrhythmias. Toxic aldehydes, known to be formed by lipid peroxidation in ischemia/reperfusion (I/R), have been shown to degranulate mast cells and activate a local RAS. OBJECTIVE: To provide an up-to-date description of the roles of ischemic preconditioning (IPC) and Gicoupled receptors in anti-RAS cardioprotection. METHODS: Ex-vivo I/R models in cavian and murine hearts, and human and murine mast cell lines in vitro. RESULTS: IPC not only drastically reduces the injury subsequent to a prolonged ischemic event, but also decreases mast cell renin release, thus affording anti-RAS cardioprotection. Similarly, activation of Gicoupled receptors, such as histamine-H4, adenosine-A3 and sphingosine-1-phosphate-S1P1 receptors, all expressed at the mast cell surface, mimic the cardioprotective anti-RAS effects of IPC. The mechanism of this action depends on the sequential activation of a specific isoform of protein kinase C, PKCε, and mitochondrial aldehyde dehydrogenase-type 2 (ALDH2). Increased ALDH2 enzymatic activity exerts a pivotal role in the sequential inhibition of aldehyde-induced mast-cell renin release, prevention of RAS activation, reduction of NE release and alleviation of reperfusion arrhythmias. CONCLUSION: These recently discovered protective pathways indicate that activation of mast-cell Gicoupled receptors and subsequent ALDH2 phosphorylation/activation represent a novel therapeutic target for the alleviation of RAS-induced cardiac dysfunctions, including ischemic heart disease and congestive heart failure.