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

Norby, Faye L.; Ns, Aberle; Kajstura, Jan; Anversa, Piero; Ren, Jun

doi:10.1677/joe.0.1800175

Cited by 50 publications

(49 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These data are consistent with our previous findings from both chemically induced and genetically predisposed rodent diabetic models (11,21,22,24,26,33). UCF-101 itself failed to alter these mechanical properties in the absence of diabetes, whereas it restored almost all STZ-induced mechanical defects with the exception of peak shortening.…”

Section: Discussionsupporting

confidence: 92%

UCF-101 mitigates streptozotocin-induced cardiomyocyte dysfunction: role of AMPK

Ren

2009

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

Li Q, Li J, Ren J. UCF-101 mitigates streptozotocin-induced cardiomyocyte dysfunction: role of AMPK. Am J Physiol Endocrinol Metab 297: E965-E973, 2009. First published August 18, 2009 doi:10.1152/ajpendo.00323.2009.-Diabetic heart disease contributes to the high mortality in diabetics, although effective clinical management is lacking. The protease inhibitor 5-[5-(2-nitrophenyl) furfuryliodine]-1,3-diphenyl-2-thiobarbituric acid (UCF-101) was reported to protect the hearts against ischemic injury. This study examined the role of UCF-101 on streptozotocin (STZ)-induced diabetic heart defect. Vehicle or UCF-101 was administrated to STZ diabetic mice, and cardiomyocyte mechanical properties were analyzed. UCF-101 reduced STZ-induced hyperglycemia and alleviated STZ-induced aberration in cardiomyocyte contractile mechanics. Diabetes dramatically decreased AMPK phosphorylation at Thr 172 of catalytic ␣-subunit, which was restored by UCF-101. Neither diabetes nor UCF-101 affected the expression of HtrA2/Omi and XIAP or caspase-3 activity. The AMPK activator resveratrol mimicked the UCF-101-induced beneficial effect against diabetic cardiac dysfunction. Mechanical properties in cardiomyocytes from the AMPKkinase-dead (KD) mice displayed markedly impaired contractile function reminiscent of diabetes. STZ injection in AMPK-KD mice failed to elicit any additional cardiomyocyte contractile defect. UCF-101 significantly downregulated the AMPK-degrading enzymes PP2A and PP2C, the effect of which was mimicked by resveratrol. Taken together, these results indicate that UCF-101 protects against STZinduced cardiac dysfunction, possibly through AMPK signaling. contractile function; diabetes; adenosine 5Ј-monophosphate-activated protein kinase MOUNTING EVIDENCE HAS INDICATED that cardiovascular complications are the leading cause of morbidity and mortality in diabetic population. With the rapidly increasing burden of diabetes mellitus worldwide coupled with cardiovascular complications, diabetic heart diseases have been the subject of intensive research over the last three decades. Although a cadre of hypoglycemic or antihyperglycemic drugs is used clinically for the management of diabetes, new classes of drugs with specific benefit on diabetic cardiomyopathy are still lacking (12,25). Recent evidence has revealed a rather unique cardioprotective role of the protease inhibitor 5-[5-(2-nitrophenyl) furfuryliodine]-1,3-diphenyl-2-thiobarbituric acid (UCF-101) (2, 17). UCF-101 is a specific inhibitor of high-temperature requirement A2 (HtrA2)/Omi, a mitochondrial serine protease released into cytosol from mitochondria to promote caspase activation by proteolyzing the antiapoptotic X chromosomelinked inhibitor of apoptosis protein (XIAP) (3). It is believed that UCF-101 elicits its protective role through antiapoptotic mechanism in myocardial ischemia-reperfusion injury and cerebral ischemia (1, 2, 17). Although recent observations from our laboratory have demonstrated that UCF-101 may be cardioprotective against experimental diabet...

show abstract

Section: Discussionsupporting

confidence: 92%

UCF-101 mitigates streptozotocin-induced cardiomyocyte dysfunction: role of AMPK

Ren

2009

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

show abstract

“…The present study revealed that hearts from diabetic rats showed significantly reduced contractility and prolonged diastole in vivo, which are hallmarks of diabetic cardiomyopathy. These findings are in agreement with other studies [26][27][28] . Consistent with their impaired cardiac function, diabetic rats developed myocardial fibrosis, the marked fibrotic regions (as observed by immunohistochemical staining), as well as deposition of collagen fibers in the interstitial spaces among cardiomyocytes (as observed by TEM), our observations are similar to those described in other reports [29,30] .…”

Section: Discussionsupporting

confidence: 94%

Involvement of RhoA/ROCK in myocardial fibrosis in a rat model of type 2 diabetes

Zhou

Wang

et al. 2011

Acta Pharmacol Sin

View full text Add to dashboard Cite

Aim: To investigate whether activation of RhoA/Rho kinase (ROCK) is involved in myocardial fibrosis in diabetic hearts. Methods: A rat model of type 2 diabetes was established using high fat diet combined with streptozotocin (30 mg/kg, ip). Animals were randomly divided into 3 groups: control rats, untreated diabetic rats that received vehicle and treated diabetic rats that received Rhokinase inhibitor fasudil hydrochloride hydrate (10 mg·kg -1 ·d -1 , ip, for 14 weeks). Cardiac contractile function was evaluated in vivo. The morphological features of cardiac fibrosis were observed using immunohistochemistry and TEM. The mRNA expression of JNK, TGFβ1, type-I, and type-III procollagen was assessed with RT-PCR. The phosphorylation of MYPT1, JNK and Smad2/3, as well as the protein levels of TGFβ1 and c-Jun, were evaluated using Western blotting. Results: In untreated diabetic rats, myocardial fibrosis was developed and the heart contractility was significantly reduced as compared to the control rats. In the hearts of untreated diabetic rats, the mRNA expression level and activity of JNK were upregulated; the expression of TGFβ1 and phosphorylation of Smad2/3 were increased. In the hearts of treated diabetic rat, activation of JNK and TGFβ/Smad was significantly decreased, myocardial fibrosis was reduced, and cardiac contractile function improved. Conclusion: The data suggest that fasudil hydrochloride hydrate ameliorates myocardial fibrosis in rats with type 2 diabetes at least in part through inhibiting the JNK and TGFβ/Smad pathways. Inhibition of RhoA/ROCK may be a novel therapeutic target for prevention of diabetic cardiomyopathy.

show abstract

“…IGF-1 may also elicit cardiac protection against diabetes involving attenuated p53 function, angiotensin II production and angiotensin receptor activation . Our studies suggested that IGF-1 may rescue the diabetes-induced reduction in SERCA protein abundance and impaired -adrenergic responsiveness (Norby et al 2002(Norby et al , 2004. In addition, diabetic tissues including hearts usually display IGF-1 resistance (Rodgers et al 1995, Kelley et al 1999, Ren et al 1999a, Ren 2000, making glucose clearing by IGF-1 largely dependent on crossreaction with the insulin receptor, which requires higher levels of IGF-1 agonist.…”

Section: Discussionmentioning

confidence: 79%

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

View full text Add to dashboard Cite

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.

show abstract

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

Cited by 50 publications

References 35 publications

UCF-101 mitigates streptozotocin-induced cardiomyocyte dysfunction: role of AMPK

UCF-101 mitigates streptozotocin-induced cardiomyocyte dysfunction: role of AMPK

Involvement of RhoA/ROCK in myocardial fibrosis in a rat model of type 2 diabetes

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

Contact Info

Product

Resources

About