Submitted on February 17, 2009
Revised on September 22, 2009
Accepted on October 2, 2009
Myocardial fibrosis and apoptosis, but not inflammation, are present in long-term experimental diabetes.
Sara Ares-Carrasco1, Belén Picatoste1, Alberto Benito-Martín1, Irene Zubiri1, Ana Belén Sanz1, María Dolores Sanchez-Miño2, A. Ortiz2, Jesus Egido3, José Tuñón1, and Óscar Lorenzo4*
1 Fundación Jiménez Díaz Hospital
2 Fundacion Jimenez Diaz
3 Fundacion Jimenez Diaz Autonoma University
4 Autonoma University
* To whom correspondence should be addressed. E-mail: olorenzo{at}fjd.es.
Aim: To study the myocardial damage secondary to long-term streptozotocin-induced type-1 Diabetes Mellitus (DM1). Methods: Normotensive and spontaneously hypertensive (SHR) rats received either streptozotocin injections or vehicle. After 22 or 6 weeks, DM1, SHR, DM1/SHR and control rats were sacrificed and the left ventricles studied by histology, Quantitative-PCR, Western Blot, ELISA and Electro-mobility Shift Assay. Cardiomyocyte cultures were also performed. Results: The expression of pro-fibrotic factors Transforming Growth Factor-
(TGF1), Connective tissue growth factor (CTGF) and matrix proteins was increased and the TGF1-linked transcription factors p-Smad3/4 and AP-1 were activated in the DM1 myocardium. Pro-apoptotic 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
B, increased inflammatory cell infiltrate and expression of the mediators [interleukin-1 (IL-1), tumor necrosis factor-
(TNF), monocyte chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1), angiotensinogen and oxidants], which were absent in long-term DM1. At this stage, the combination of DM1 and hypertension resulted in non-significant additive effects. Moreover, the coexistence of DM1 blunted the inflammatory response to hypertension. Anti-inflammatory IL-10 and anti-oxidants 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, TGF1 and catalase blocked the glucose-stimulated expression of pro-inflammatory genes. Conclusions: 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 pro-inflammatory factors and expression of anti-inflammatory and anti-oxidant molecules may underlie this effect.
