Modulation of Cardiac Ca2+Channels by IGF1

Solem, Michele; Thomas, Andrew P.

doi:10.1006/bbrc.1998.9626

Cited by 29 publications

(23 citation statements)

References 26 publications

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“…It has been recently reported that IGF-1 increases intracellular Ca 2+ , possibly via a PKC-dependent mechanism. 20 In the present study, IGF-1-induced calcineurin activation was blocked by PKC inhibitors (Fig 2) and so we speculate that IGF-1 elevates intracellular Ca 2+ by a PKC-related mechanism with resultant activation of calcineurin. We demonstrated that IGF-1 markedly increased calcineurin activity, which was completely blocked by pre-treatment with cyclosporine A (Fig 2).…”

Section: Discussionsupporting

confidence: 60%

“…14- 19 Molkentin et al 14 have demonstrated that cardiac-specific overexpression of calcineurin and NFAT-3 in transgenic mice resulted in marked cardiac hypertrophy in vivo, but the implication of calcineurin is still controversial in conventional animal models of cardiac hypertrophy produced by pressure-overload and is as yet unknown in human hearts. 15,16 It has recently been reported that IGF-1 increases the intracellular Ca 2+ level, possibly via a protein kinase C (PKC) related mechanism, 20 so IGF-1 may activate calcineurin in cardiomyocytes. Thus the present study was designed to test the hypothesis that IGF-1 promotes hypertrophy of the adult cardiomyocyte by a calcineurin-mediated pathway.…”

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confidence: 99%

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Role of Calcineurin in Insulin-Like Growth Factor-1-Induced Hypertrophy of Cultured Adult Rat Ventricular Myocytes.

et al. 2001

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ongestive heart failure is a major and growing public health problem with a high mortality rate. 1 Myocardial hypertrophy is an adaptive response to mechanical and humoral stimuli to normalize wall stress and maintain cardiac performance. 2 However, if the stimulus for cardiac hypertrophy is sufficiently intense and prolonged, decompensated hypertrophy ensues and ultimately leads to congestive heart failure. Although previous studies have demonstrated that a variety of factors, including hemodynamic overload (mechanical stress), genetic factors and neurohumoral factors, account for the transition from compensated hypertrophy to decompensated failure, the precise mechanisms of this pathological process are not fully understood. 3 Mechanical stress on cardiomyocytes induces hypertrophic responses, including the activation of protein kinases, re-capitulation of fetal gene expression and protein synthesis. 4 There is also a growing body of evidence that humoral factors induce cardiomyocyte hypertrophy 3 and these include (1) cytokines such as interleukin-6, 5 cardiotrophin 1, 6 and leukemia inhibitory factor, 7 (2) growth factors such as insulin-like growth factor-1 (IGF-1) 8 and fibroblast growth factor, 9 and (3) vasoactive agents such as Japanese Circulation Journal Vol.65, September 2001 1-adrenergic agonist, 10 endothelin-1, 11 and angiotensin II. 12 Of these, IGF-1 has a potent hypertrophic effect on cultured neonatal rat cardiomyocytes by activating a Ras/Raf-1/ extracellular signal-regulated kinase (ERK) pathway. 13 However, there is little information regarding the role of IGF-1 in adult cardiomyocyte hypertrophy.Recently, the Ca 2+ -dependent phosphatase, calcineurin, has attracted attention as a new signaling molecule for cardiomyocyte hypertrophy through its activation of the nuclear factor of activated T cells (NFAT)-3. [14][15][16][17][18][19] Molkentin et al 14 have demonstrated that cardiac-specific overexpression of calcineurin and NFAT-3 in transgenic mice resulted in marked cardiac hypertrophy in vivo, but the implication of calcineurin is still controversial in conventional animal models of cardiac hypertrophy produced by pressure-overload and is as yet unknown in human hearts. 15,16 It has recently been reported that IGF-1 increases the intracellular Ca 2+ level, possibly via a protein kinase C (PKC) related mechanism, 20 so IGF-1 may activate calcineurin in cardiomyocytes. Thus the present study was designed to test the hypothesis that IGF-1 promotes hypertrophy of the adult cardiomyocyte by a calcineurin-mediated pathway. Methods Isolation and Culture of Adult Rat Ventricular Myocytes (ARVM)We anesthetized 14-16-week-old adult male SpragueDawley rats with sodium pentobarbital (60 mg/kg ip), and the hearts were excised and placed in Ca The present study examined the role of calcineurin in insulin-like growth factor (IGF)-1-induced hypertrophy in primary cultures of adult rat ventricular myocytes (ARVM), prepared from the ventricles of 14-16-week-old male Sprague-Dawley rats. The effects of seve...

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Section: Discussionsupporting

confidence: 60%

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confidence: 99%

Role of Calcineurin in Insulin-Like Growth Factor-1-Induced Hypertrophy of Cultured Adult Rat Ventricular Myocytes.

et al. 2001

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“…Several scenarios have been speculated for IGF-1-induced cardiac protection against stress such as diabetes in addition to its well established action on glucose transport and lipid metabolism. For example, IGF-1 may regulate membrane ionic channels responsible for cardiac excitation-contraction coupling (Solem & Thomas 1998). IGF-1 may also elicit cardiac protection against diabetes involving attenuated p53 function, angiotensin II production and angiotensin receptor activation .…”

Section: Discussionmentioning

confidence: 99%

Inhibition of PI-3 kinase/Akt/mTOR, but not calcineurin signaling, reverses insulin-like growth factor I-induced protection against glucose toxicity in cardiomyocyte contractile function

Fang²,

Aberle³

et al. 2005

Journal of Endocrinology

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Insulin-like growth factor-I (IGF-1) ameliorates cardiac dysfunction in diabetes although the mechanism of action remains poorly understood. This study examined the role of PI-3 kinase/Akt/mammalian target of rapamycin (mTOR) and calcineurin pathways in cardiac effects of IGF-1 against glucose toxicity. Adult rat ventricular myocytes were cultured for 8 h with either normal (NG, 5·5 mM) or high (HG, 25·5 mM) glucose, in the presence or absence of IGF-1 (10-500 nM), the PI-3 kinase/Akt inhibitor LY294002 (10 µM), the mTOR inhibitor rapamycin (20 µM) or the calcineurin inhibitors cyclosporin A (5 µM) or FK506 (10 mg/l). Mechanical properties were evaluated using an IonOptix MyoCam system. HG depressed peak shortening (PS), reduced maximal velocity of shortening/relengthening ( dl/dt) and prolongs timeto-90% relengthening (TR 90 ), which were abolished by IGF-1 (100 and 500 nM). Interestingly, the IGF-1-elicited protective effect against HG was nullified by either LY294002 or rapamycin, but not by cyclosporine A or FK506. None of the inhibitors affected cell mechanics. Western blot analysis indicated that HG and IGF-1 stimulated phosphorylation of Akt and mTOR. HG also activated p70s6k and suppressed GSK-3 phosphorylation. However, the HG-induced alterations in phosphorylation of Akt, mTOR, p70s6k and GSK-3 were significantly reversed by IGF-1. Protein expression of Akt, mTOR, p70s6k, GSK-3 , SERCA2a and phospholamban was unaffected by HG, IGF-1 or rapamycin. Rapamycin significantly enhanced Akt phosphorylation whereas it inhibited mTOR phosphorylation. Collectively, our data suggest that IGF-1 may provide cardiac protection against glucose in part through a PI-3 kinase/Akt/mTOR/ p70s6k-dependent and calcineurin-independent pathway.

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“…In addition to its beneficial effect on glucose transport and lipid metabolism, other scenarios have been speculated for IGF-I-induced cardiac protection against stress such as diabetes. IGF-I has been demonstrated to directly regulate membrane ionic channels responsible for cardiac excitation-contraction coupling (Guo et al 1997, Solem & Thomas 1998. Recent evidence suggested that IGF-I-induced cardiac protection against diabetes may involve attenuated p53 function, angiotensin II production and angiotensin receptor activation (Kajstura et al 2001).…”

Section: Discussionmentioning

confidence: 99%

Transgenic overexpression of insulin-like growth factor I prevents streptozotocin-induced cardiac contractile dysfunction and beta-adrenergic response in ventricular myocytes

Norby¹,

Ns²,

Kajstura³

et al. 2004

Journal of Endocrinology

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Diabetic cardiomyopathy is characterized by cardiac dysfunction and altered level/function of insulin-like growth factor I (IGF-I). Both endogenous and exogenous IGF-I have been shown to effectively alleviate diabetes-induced cardiac dysfunction and oxidative stress. This study was designed to examine the effect of cardiac overexpression of IGF-I on streptozotocin (STZ)-induced cardiac contractile dysfunction in mouse myocytes. Both IGF-I heterozygous transgenic mice and their wild-type FVB littermates were made diabetic with a single injection of STZ (200 mg/kg, i.p.) and maintained for 2 weeks. The following mechanical indices were evaluated in ventricular myocytes: peak shortening (PS), time-to-PS (TPS), time-to-90% relengthening (TR 90 ) and maximal velocity of shortening/ relengthening ( dL/dt , were prevented by the IGF-I transgene. In addition, myocytes from STZ-treated FVB mice displayed an attenuated contractile response to the -adrenergic agonist isoproterenol, which was restored by the IGF-I transgene. Contractile response to the -adrenergic agonist phenylephrine and angiotensin II was not affected by either STZ treatment or IGF-I. These results validate the beneficial role of IGF-I in diabetic cardiomyopathy, possibly due to an improved -adrenergic response.

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Modulation of Cardiac Ca2+Channels by IGF1

Cited by 29 publications

References 26 publications

Role of Calcineurin in Insulin-Like Growth Factor-1-Induced Hypertrophy of Cultured Adult Rat Ventricular Myocytes.

Role of Calcineurin in Insulin-Like Growth Factor-1-Induced Hypertrophy of Cultured Adult Rat Ventricular Myocytes.

Inhibition of PI-3 kinase/Akt/mTOR, but not calcineurin signaling, reverses insulin-like growth factor I-induced protection against glucose toxicity in cardiomyocyte contractile function

Transgenic overexpression of insulin-like growth factor I prevents streptozotocin-induced cardiac contractile dysfunction and beta-adrenergic response in ventricular myocytes

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