Abstract 14133: CTRPs, A Novel Therapeutic Target Against Myocardial Ischemia/Reperfusion Injury
The C1q/TNF-related proteins (CTRP1–10) are a group of newly identified adipocytokines that share structural similarity to adiponectin (APN), a potent cardioprotective molecule. Recent in vitro studies have demonstrated that CTRPs possess similar metabolic regulatory actions as APN. However, biologic functions of CTRP in the cardiovascular system remain completely unknown. Adult male mice were subjected to 30 min myocardial ischemia (MI) followed by 24 h reperfusion (R) or sham MI/R. CTRP expression (mRNA and protein) was determined in multiple organs. All CTRPs, except CTRP10 which was human specific, were expressed in adipocytes as well as in cardiac tissue. Interestingly, although CTRP expression levels are much lower (<1/10,000) than APN in adipocytes, CTRP expression levels exceed APN in cardiomyocytes (2.46–88 fold), the highest being CTRP9. MI/R significantly inhibited CTRP1, 7, and 9 expression in both adipocytes and cardiomyocytes (P<0.01), and reduced their plasma levels (P<0.01). To define the physiologic/pathologic significance of CTRPs and its reduction by MI/R, the effect of CTRP supplementation on MI/R injury was determined. In isolated adult mouse cardiomyocytes subjected to simulated ischemic/reperfusion, recombinant globular domain of CTRP1 and 9 (2μg/ml) significantly reduced LDH release (−14.5% and -33%, P<0.05 and 0.01 vs. vehicle) and inhibited caspase-3 activity (−47.9% and -41.6%, P<0.01). However, CTRP2, 3, 5, and 7 were ineffective in reducing myocardial injury. To confirm the cardioprotective effect of CTRP1 and 9 in a real pathologic model, adult male mice subjected to MI/R were treated with CTRP1 and 9 (3μg/g, 10 min before R via IP injection). Experimental results showed that administration of CTRP1 and 9 significantly protected against cardiac MI/R injury as evidenced by reduced infarct size (−44.4% and -62.9%, P<0.01 vs. vehicle) and improved cardiac function (dP/dtmax +64.3% and +56.9%, P<0.01 vs. vehicle; -dP/dtmax +76.0% and +61.3%, P<0.01 vs. vehicle; LVEDP -68.3% and -46.7%, P<0.01 vs. vehicle). In conclusion, we have demonstrated for the first time that MI/R significantly inhibited CTRP expression, and that CTRP1 and 9 supplementation may provide novel strategies for ameliorating MI/R injury.
- © 2010 by American Heart Association, Inc.