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

Abstract

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 (PϽ0.05). 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 (PϽ0.01), 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 (PϽ0.01). 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 (PϽ0.01). Conclusions-These

Follistatin-like 1, a Secreted Muscle Protein, Promotes Endothelial Cell Function and Revascularization in Ischemic Tissue through a Nitric-oxide Synthase-dependent Mechanism

“…In agreement with the current study, we recently reported that Fstl1 is up-regulated during cardiac hypertrophy (16). In this study, Fstl1 was shown to activate Akt signaling in cardiac myocytes and inhibit apoptosis.…”

“…HUVECs were infected with adenoviral constructs encoding mouse Fstl1 (Ad-Fstl1) (16), or Ad-␤-gal at a multiplicity of infection (m.o.i.) of 10 for 8 h and placed in endothelial cell basal medium-2 (Lonza) without serum for the indicated lengths of time.…”

“…Transduction of cancer cell lines with Fstl1 has been shown to result in suppression of growth and invasiveness (14,15). Recently, we demonstrated that Fstl1 is up-regulated in myocardium in cardiac-specific Akt1 transgenic (TG) mice and that Fstl1 functions as a cardioprotective molecule with anti-apoptotic actions in cardiac myocytes (16). To date, however, the secretion of Fstl1 by skeletal muscle has not been investigated, and no functional analysis of Fstl1 has been performed in the setting of vascular disease.…”

Myokines in insulin resistance and type 2 diabetes

“…Its expression is induced in the heart by ischaemic insults, and systemic administration of FSTL1 protects the heart from ischaemia/reperfusion injury [134]. Shimano et al have described cardiac FSTL1 as functioning as an auto-/paracrine regulatory factor that prevents myocyte hypertrophic growth and the loss of ventricular performance in response to pressure overload [133].…”

Cardiac Myocyte-Derived Follistatin-Like 1 Prevents Renal Injury in a Subtotal Nephrectomy Model

“…13,14 Previously, we reported that Fstl1 is a cardiokine upregulated by various heart stresses, including cardiac ischemia/reperfusion injury, pressure overload, and myocardial infarction. 15,16 Cardiac myocytederived Fstl1 reduces pathologic cardiac hypertrophy induced by pressure overload. 16 Systemic administration of Fstl1 improves myocardial ischemia/reperfusion damage through reduction of myocyte apoptosis and inflammatory responses.…”