Therapeutic Impact of Follistatin-like 1 on Myocardial Ischemic Injury in Preclinical Animal Models
Background—Acute coronary syndrome (ACS) is a leading cause of death in developed countries. Follistatin-like 1 (FSTL1) is a myocyte-derived secreted protein, which is upregulated in the heart in response to ischemic insult. Here, we investigated the therapeutic impact of FSTL1 on acute cardiac injury in small and large preclinical animal models of ischemia/reperfusion (I/R) and dissected its molecular mechanism.
Methods and Results—Administration of human FSTL1 protein significantly attenuated myocardial infarct size in a mouse or pig model of I/R, which was associated with reduction of apoptosis and inflammatory responses in the ischemic heart. Administration of FSTL1 enhanced the phosphorylation of AMP-activated protein kinase (AMPK) in the I/R-injured heart. In cultured cardiac myocytes, FSTL1 suppressed apoptosis in response to hypoxia/reoxygenation and LPS-stimulated expression of pro-inflammatory genes through its ability to activate AMPK. I/R led to enhancement of bone morphogenetic protein-4 (BMP-4) expression and Smad1/5/8 phosphorylation in the heart, and FSTL1 suppressed the increased phosphorylation of Smad1/5/8 in ischemic myocardium. Treatment of cardiac myocytes with FSTL1 abolished the BMP-4-stimulated increase in apoptosis, Smad1/5/8 phosphorylation and pro-inflammatory gene expression. In cultured macrophages, FSTL1 diminished LPS-stimulated expression of pro-inflammatory genes via activation of AMPK, and also abolished BMP-4-dependent induction of pro-inflammatory mediators.
Conclusions—Our data indicate that FSTL1 can prevent myocardial I/R injury by inhibiting apoptosis and inflammatory response through modulation of AMPK- and BMP-4-dependent mechanisms, suggesting that FSTL1 could represent a novel therapeutic target for ACS.
- Received April 27, 2012.
- Accepted August 21, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited