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(Circulation. 2008;117:3099-3108.)
© 2008 American Heart Association, Inc.

Molecular Cardiology

Follistatin-Like 1 Is an Akt-Regulated Cardioprotective Factor That Is Secreted by the Heart

Yuichi Oshima, MD, PhD; Noriyuki Ouchi, MD, PhD; Kaori Sato, MD, PhD; Yasuhiro Izumiya, MD, PhD; David R. Pimentel, MD; Kenneth Walsh, PhD

From Molecular Cardiology, Whitaker Cardiovascular Institute (Y.O., N.O., K.S., Y.I., K.W.), and the Myocardial Biology Unit (D.R.P.), Boston University Medical Campus, Boston, Mass.

Correspondence to Kenneth Walsh, PhD, Molecular Cardiology/Whitaker Cardiovascular Institute, Boston University Medical School, 700 Albany St, W611, Boston, MA 02118. E-mail kxwalsh{at}bu.edu

Received January 18, 2008; accepted April 9, 2008.

Background— The Akt protein kinase is an important mediator of cardiac myocyte growth and survival. To identify factors with novel therapeutic applications in cardiac diseases, we focused on the identification of factors secreted from Akt1-activated cells that have cardioprotective effects through autocrine/paracrine mechanisms.

Methods and Results— Using an inducible Akt1 transgenic mouse model, we have found that follistatin-like 1 (Fstl1) protein and transcript expression are increased 4.0- and 2.0-fold, respectively, by Akt activation in the heart (P<0.05). Fstl1 transcript was also upregulated in response to myocardial stresses including transverse aortic constriction, ischemia/reperfusion injury, and myocardial infarction. Adenovirus-mediated overexpression of Fstl1 protected cultured neonatal rat ventricular myocytes from hypoxia/reoxygenation-induced apoptosis (P<0.01), and this protective effect was dependent on the upregulation of both Akt and ERK activities. Conversely, knockdown of Fstl1 in cardiac myocytes decreased basal Akt signaling and increased the frequency of apoptotic death in vitro (P<0.01). The intravenous administration of an adenoviral encoding Fstl1 to mice resulted in a 66.0% reduction in myocardial infarct size after ischemia/reperfusion injury that was accompanied by a 70.9% reduction in apoptosis in the heart (P<0.01).

Conclusions— These results indicate that Fstl1 is a cardiac-secreted factor that functions as an antiapoptotic protein. Fstl1 could play a role in myocardial maintenance and repair in response to harmful stimuli.

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CLINICAL PERSPECTIVE

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Clinical Summaries
Circulation 2008 117: 3055-3056. [Full Text]