PT  - JOURNAL ARTICLE
AU  - Alice Marino
AU  - Takuya Sakamoto
AU  - Pablo A. Robador
AU  - Kengo Tomita
AU  - Roberto Levi
TI  - S1P receptor 1-Mediated Anti–Renin-Angiotensin System Cardioprotection: Pivotal Role of Mast Cell Aldehyde Dehydrogenase Type 2
AID  - 10.1124/jpet.117.241976
DP  - 2017 Aug 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 230--242
VI  - 362
IP  - 2
4099  - http://jpet.aspetjournals.org/content/362/2/230.short
4100  - http://jpet.aspetjournals.org/content/362/2/230.full
SO  - J Pharmacol Exp Ther2017 Aug 01; 362
AB  - 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 Gi-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 Gi-coupled S1P1 receptors (S1P1R) on MC. We report that activation of Gi-coupled S1P1R in cardiac MC confers IPC-like anti-RAS cardioprotection due to S1P1R-mediated inhibition of I/R-induced cardiac MC degranulation and renin release. This results from an initial translocation of protein kinase C subtype-ε 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 S1P1R 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.