Regulation of Cardiomyocyte Apoptotic Signaling by Insulin-like Growth Factor I

Abstract

Apoptosis is regulated by specific intracellular signaling pathways. The development of cardiomyopathy involves the apoptosis of cardiomyocytes; however, the details of their apoptotic signaling are not yet known. Insulin-like growth factor I (IGF I) is an important survival growth factor for myocardium and other tissues, but the effects of IGF I on apoptotic signaling remain largely unknown. To study apoptotic signaling pathways in cardiomyocytes and to understand IGF I actions on the apoptotic signaling of cardiac muscle cells, we have defined the effects of IGF I on Bcl-2, Bax, caspase 3, DNA fragmentation, and cell survival in primary cardiomyocytes. Compared with Bax levels, the levels of Bcl-2 were found to be quite low in these cells. Serum withdrawal and doxorubicin reduced cell viability, increased fragmentation of DNA, increased cellular contents of Bax, and activated caspase 3. IGF I enhanced cell viability, suppressed DNA fragmentation, attenuated Bax induction, and suppressed caspase 3 activation. The levels of Bcl-2-associated Bax were increased after serum withdrawal and incubation with doxorubicin and were reduced by IGF I. Thus, cardiomyocyte apoptosis induced by serum withdrawal and doxorubicin likely results, in part, from the induction of Bax and activation of caspase 3, but IGF I may inhibit cardiomyocyte apoptosis by attenuating Bax induction and caspase 3 activation. These findings provide new insight into the mechanisms of cardiomyocytes apoptosis and may help elucidate how IGF I modulates apoptotic signaling in cardiac muscle.

A Novel Cardiomyocyte-enriched MicroRNA, miR-378, Targets Insulin-like Growth Factor 1 Receptor

“…IGF1R signaling is also found to be essential in inducing physiological growth associated with exercise-induced cardiac hypertrophy (24). Exogenous administration of IGF1 in vivo reduces cardiomyocyte apoptosis in response to stress injury (25)(26)(27)(28). Intriguingly, genetic studies conducted in murine models indicate that an excess of IGF1 signaling may also trigger cardiac dysfunction (29).…”

Adenoviral Gene Transfer of Activated Phosphatidylinositol 3′-Kinase and Akt Inhibits Apoptosis of Hypoxic Cardiomyocytes In Vitro

“…18 Akt can inhibit caspase-mediated cell death through multiple mechanisms, 6,7 including release of antiapoptotic Bcl-family members. 5 Of note, adenoviral overexpression of Bcl-2 in cardiomyocytes is itself sufficient to prevent p53-mediated apoptosis.…”

Akt Promotes Survival of Cardiomyocytes In Vitro and Protects Against Ischemia-Reperfusion Injury in Mouse Heart

“…8,19 To document the cytoprotective effects of IGF-1 under the conditions of our assays, neonatal rat cardiac myocytes were cultured in serum-free medium in the presence or absence of IGF-1, and cell viability was determined by trypan blue exclusion at various time points ( Figure 1A). In the absence of IGF-1, cardiac myocyte cultures displayed a time-dependent decrease in viability with >50% loss of live cells by 72 hours.…”

“…7 More recently, it has been shown that IGF-1 functions as a cell survival factor for cultured cardiac myocytes exposed to doxorubicin in the absence of serum. 8 Therefore, analysis of the IGF-1 signaling pathways, especially with respect to cell survival, may lead to the development of clinical strategies to treat heart disease.…”