IGF-1 0verexpression inhibits the development of diabetic cardiomyopathy and angiotensin II-mediated oxidative stress

Jan Kajstura, Fabio Fiordaliso, Anna Maria Andreoli, Baosheng Li, Stefano Chimenti, Marvin S. Medow, Federica Limana, Bernardo Nadal-Ginard, Annarosa Leri, Piero Anversa

Research output: Contribution to journalArticle

Abstract

Stimulation of the local renin-angiotensin system and apoptosis characterize the diabetic heart. Because IGF-1 reduces angiotensin (Ang) II and apoptosis, we tested whether streptozotocin-induced diabetic cardiomyopathy was attenuated in IGF-1 transgenic mice (TGM). Diabetes progressively depressed ventricular performance in wild-type mice (WTM) but had no hemodynamic effect on TGM. Myocyte apoptosis measured at 7 and 30 days after the onset of diabetes was twofold higher in WTM than in TGM. Myocyte necrosis was apparent only at 30 days and was more severe in WTM. Diabetic nontransgenic mice lost 24% of their ventricular myocytes and showed a 28% myocyte hypertrophy; both phenomena were prevented by IGF-1. In diabetic WTM, p53 was increased in myocytes, and this activation of p53 was characterized by upregulation of Bax, angiotensinogen, Ang type 1 (AT1) receptors, and Ang II. IGF-1 overexpression decreased these biochemical responses. In vivo accumulation of the reactive O2 product nitrotyrosine and the in vitro formation of H2O2-̇OH in myocytes were higher in diabetic WTM than TGM. Apoptosis in vitro was detected in myocytes exhibiting high H2O2-̇OH fluorescence, and apoptosis in vivo was linked to the presence of nitrotyrosine. H2O2-̇OH generation and myocyte apoptosis in vitro were inhibited by the AT1 blocker losartan and the O2 scavenger Tiron. In conclusion, IGF-1 interferes with the development of diabetic myopathy by attenuating p53 function and Ang II production and thus AT1 activation. This latter event might be responsible for the decrease in oxidative stress and myocyte death by IGF-1.

Original languageEnglish
Pages (from-to)1414-1424
Number of pages11
JournalDiabetes
Volume50
Issue number6
Publication statusPublished - 2001

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Kajstura, J., Fiordaliso, F., Andreoli, A. M., Li, B., Chimenti, S., Medow, M. S., Limana, F., Nadal-Ginard, B., Leri, A., & Anversa, P. (2001). IGF-1 0verexpression inhibits the development of diabetic cardiomyopathy and angiotensin II-mediated oxidative stress. Diabetes, 50(6), 1414-1424.