title: Myocardial fibrosis and apoptosis, but not inflammation, are present in long-term experimental diabetes.
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-beta (TGF-beta1), connective tissue growth factor, and matrix proteins was increased, and the TGF-beta1-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-kappaB, increased inflammatory cell infiltrate, and expression of the mediators [interleukin-1beta (IL-1beta), tumor necrosis factor-alpha, 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-beta1, 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.
authors.affiliation: Vascular Pathology Laboratory, Fundación Jiménez Díaz Hospital, Autónoma University, Av. Reyes Católicos 2, Madrid 28040, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Ares-Carrasco
authors.forename: B
authors.initials: B
authors.lastname: Picatoste
authors.forename: A
authors.initials: A
authors.lastname: Benito-Martín
authors.forename: I
authors.initials: I
authors.lastname: Zubiri
authors.forename: A B
authors.initials: AB
authors.lastname: Sanz
authors.forename: M D
authors.initials: MD
authors.lastname: Sánchez-Niño
authors.forename: A
authors.initials: A
authors.lastname: Ortiz
authors.forename: J
authors.initials: J
authors.lastname: Egido
authors.forename: J
authors.initials: J
authors.lastname: Tuñón
authors.forename: O
authors.initials: O
authors.lastname: Lorenzo
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D009202:Cardiomyopathies / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005355:Fibrosis; D006973:Hypertension / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013997:Time Factors
chemical_list: D000975:Antioxidants; D051017:Apoptosis Regulatory Proteins; D015415:Biomarkers; D016207:Cytokines; D016326:Extracellular Matrix Proteins; D018836:Inflammation Mediators