Journal
CIRCULATION
Volume 117, Issue 24, Pages 3099-3108Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.108.767673
Keywords
apoptosis; myocytes; reperfusion
Funding
- NHLBI NIH HHS [R01 HL077774-04, R01 HL086785-18, R01 HL086785, P01 HL081587-04, HL86785, HL77774, R01 HL116591, K08 HL071563, HL71563, P01 HL081587, HL81587, R01 HL077774] Funding Source: Medline
- NIA NIH HHS [R01 AG015052, R37 AG015052, AG15052, R01 AG015052-05] Funding Source: Medline
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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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