Journal
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Volume 362, Issue 2, Pages 230-242Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/jpet.117.241976
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Funding
- National Institutes of Health National Heart, Lung, and Blood Institute [HL034215]
- American Heart Association
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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-epsilon 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(star)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)Rmay represent a new pharmacologic and therapeutic target for the direct alleviation of RAS-induced cardiac dysfunctions, including ischemic heart disease and congestive heart failure.
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