Myocardial fibrosis and apoptosis, but not inflammation, are present in long-term experimental diabetes
- 1 December 2009
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Heart and Circulatory Physiology
- Vol. 297 (6), H2109-H2119
- https://doi.org/10.1152/ajpheart.00157.2009
Abstract
The aim of this paper is to study the myocardial damage secondary to long-term streptozotocin-induced type 1 diabetes mellitus (DM1). Normotensive and spontaneously hypertensive rats (SHR) received either streptozotocin injections or vehicle. After 22 or 6 wk, DM1, SHR, DM1/SHR, and control rats were killed, and the left ventricles studied by histology, quantitative PCR, Western blot, ELISA, and electromobility shift assay. Cardiomyocyte cultures were also performed. The expression of profibrotic factors, transforming growth factor-β (TGF-β1), connective tissue growth factor, and matrix proteins was increased, and the TGF-β1-linked transcription factors phospho-Smad3/4 and activator protein-1 were activated in the DM1 myocardium. Proapoptotic molecules FasL, Fas, Bax, and cleaved caspase-3 were also augmented. Myocardial injury in long-term hypertension shared these features. In addition, hypertension was associated with activation of NF-κB, increased inflammatory cell infiltrate, and expression of the mediators [interleukin-1β (IL-1β), tumor necrosis factor-α, monocyte chemoattractant protein 1, vascular cell adhesion molecule 1, angiotensinogen, and oxidants], which were absent in long-term DM1. At this stage, the combination of DM1 and hypertension resulted in nonsignificant additive effects. Moreover, the coexistence of DM1 blunted the inflammatory response to hypertension. Anti-inflammatory IL-10 and antioxidants were induced in long-term DM1 and DM1/SHR hearts. Myocardial inflammation was, however, observed in the short-term model. In cultured cardiomyocytes, IL-10, TGF-β1, and catalase blocked the glucose-stimulated expression of proinflammatory genes. Fibrosis and apoptosis are features of long-term myocardial damage in experimental DM1. Associated hypertension does not induce additional changes. Myocardial inflammation is present in hypertension and short-term DM1, but is not a key feature in long-term DM1. Local reduction of proinflammatory factors and expression of anti-inflammatory and antioxidant molecules may underlie this effect.Keywords
This publication has 40 references indexed in Scilit:
- Diabetic cardiomyopathy: effects of fenofibrate and metformin in an experimental model – the Zucker diabetic ratCardiovascular Diabetology, 2009
- Regulation of autoimmune inflammation by pro-inflammatory cytokinesImmunology Letters, 2008
- Impaired cytokine production by peripheral blood mononuclear cells in type 1 diabetic patientsDiabetes & Metabolism, 2007
- Diabetic Cardiomyopathy RevisitedCell Metabolism, 2007
- Effect of β-adrenergic and renin–angiotensin system blockade on myocyte apoptosis and oxidative stress in diabetic hypertensive ratsLife Sciences, 2007
- Alterations in the diabetic myocardial proteome coupled with increased myocardial oxidative stress underlies diabetic cardiomyopathyJournal of Molecular and Cellular Cardiology, 2007
- Vital imaging of H9c2 myoblasts exposed to tert-butylhydroperoxide – characterization of morphological features of cell deathBMC Cell Biology, 2007
- Glycogen synthase kinase 3β together with 14-3-3 protein regulates diabetic cardiomyopathy: Effect of losartan and tempolFEBS Letters, 2006
- Animal models of diabetes mellitusDiabetic Medicine, 2005
- Diabetes per se and metabolic state influence gene expression in tissue‐dependent manner of BB/OK ratsDiabetes/Metabolism Research and Reviews, 2004