Description: In the ischemic-reperfused (I/R) heart, renin-containing mast cells (MC) release enzymatically active renin, activating a local renin-angiotensin system (RAS), causing excessive norepinephrine release and arrhythmic dysfunction. Activation of G i -receptors on MC and/or ischemic preconditioning (IPC) prevent renin release, thus providing anti-RAS cardioprotection. We questioned whether sphingosine-1-phosphate (S1P), a sphingolipid produced in the I/R heart, might afford anti-RAS cardioprotection by activating G i -coupled S1P 1 receptors (S1P 1 R) on MC. We report that activation of G i -coupled S1P 1 R in cardiac MC confers IPC-like anti-RAS cardioprotection due to S1P 1 R-mediated inhibition of I/R-induced cardiac MC degranulation and renin release. This results from an initial translocation of protein kinase C subtype- and subsequent activation of aldehyde dehydrogenase type 2 (ALDH2), culminating in the elimination of the MC-degranulating effects of acetaldehyde and other toxic species produced during I/R. Inhibition of toxic aldehydes-induced MC-renin release prevents local RAS activation, reduces infarct size, and alleviates arrhythmias. Notably, these cardioprotective effects are lacking in hearts and MC from gene-targeted knock-in mice (ALDH2*2) in which ALDH2 enzymatic activity is maximally reduced. Thus, ALDH2 appears to play a pivotal role in this protective process. Our findings suggest that MC S1P 1 R may represent a new pharmacologic and therapeutic target for the direct alleviation of RAS-induced cardiac dysfunctions, including ischemic heart disease and congestive heart failure.

Description: We previously discovered that oral treatment with AC261066, a synthetic selective agonist for the retinoic acid β 2 -receptor, decreases oxidative stress in the liver, pancreas, and kidney of mice fed a high-fat diet (HFD). Since hyperlipidemic states are causally associated with myocardial ischemia and oxidative stress, we have now investigated the effects of AC261066 in an ex vivo ischemia/reperfusion (I/R) injury model in hearts of two prototypic dysmetabolic mice. We found that a 6-week oral treatment with AC261066 in both genetically hypercholesterolemic (ApoE –/– ) and obese (HFD-fed) wild-type mice exerts protective effects when their hearts are subsequently subjected to I/R ex vivo in the absence of added drug. In ApoE –/– mice this cardioprotection ensued without hyperlipidemic changes. Cardioprotection consisted of attenuation of infarct size, diminution of norepinephrine (NE) spillover, and alleviation of reperfusion arrhythmias. This cardioprotection was associated with a reduction in oxidative stress and mast cell (MC) degranulation. We suggest that the reduction in myocardial injury and adrenergic activation, and the antiarrhythmic effects, result from decreased formation of oxygen radicals and toxic aldehydes known to elicit the release of MC-derived renin, promoting the activation of the local renin-angiotensin system leading to enhanced NE release and reperfusion arrhythmias. Because these beneficial effects of AC261066 occurred at the ex vivo level following oral drug treatment, our data suggest that AC261066 could be viewed as a therapeutic means to reduce I/R injury of the heart, and potentially also be considered in the treatment of other cardiovascular ailments such as chronic arrhythmias and cardiac failure.