Follistatin-like 1 is an Akt-regulated cardioprotective factor that is secreted by the heart.
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.


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.
Molecular Cardiology/Whitaker Cardiovascular Institute, Boston University Medical School, 700 Albany St, W611, Boston, MA 02118, USA.
Yuichi
Y
Oshima
Noriyuki
N
Ouchi
Kaori
K
Sato
Yasuhiro
Y
Izumiya
David R
DR
Pimentel
Kenneth
K
Walsh
D000818:Animals; D002316:Cardiotonic Agents; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000235:genetics; D038702:Follistatin-Related Proteins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D006321:Heart / Q000502:physiology*; D006801:Humans; D008285:Major Histocompatibility Complex / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D015427:Reperfusion Injury / Q000235:genetics; D014158:Transcription, Genetic; D015854:Up-Regulation
D002316:Cardiotonic Agents; D018076:DNA, Complementary; D038702:Follistatin-Related Proteins; C448720:Fstl1 protein, mouse; D034741:RNA, Small Interfering; C448719:Fstl1 protein, rat; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt