title: Diabetic basement membrane thickening does not occur in myocardial capillaries of transgenic mice when metallothionein is overexpressed in cardiac myocytes.
abstract: Diabetic cardiomyopathy is a clinically distinct disease characterized by impaired cardiac function as a result of reduced contractility and hypertension-induced athero- or arteriosclerosis. This may be due either to generalized vascular disease, tissue-based injury such as focal cardiomyocyte dysmorphia, or microvascular damage manifested by myocardial capillary basement membrane (CBM) thickening. Hyperglycemia-driven increases in reactive oxygen species (ROS) have been proposed to contribute to such damage. To address this hypothesis, we utilized light (LM) and transmission electron microscopy (TEM) to demonstrate cardiomyocyte morphology and myocardial CBM thickness in the left ventricles of four mouse genotypes: FVB (background Friend virus B controls), OVE (transgenic diabetics), Mt [transgenics with targeted overexpression of the antioxidant protein metallothionein (MT) in cardiomyocytes], and OVEMt (bi-transgenic cross of OVE and Mt) animals. Mice were prepared for morphometric analysis by vascular perfusion. Focal myocardial disorganization was identified in OVE mice but not in the remaining genotypes. Not unexpectedly, myocardial CBM thickness was increased significantly in OVE relative to FVB (P < 0.05) and Mt (P < 0.05) animals (+28% and +39.5%, respectively). Remarkably, however, OVEMt myocardial CBMs showed no increase in width; rather they were ~3% thinner than FVB controls. Although the molecular mechanisms regulating CBM width remain elusive, it seems possible that despite a significant hyperglycemic environment, MT antioxidant activity may mitigate local oxidative stress and reduce downstream excess microvascular extracellular matrix (ECM) formation. In addition, the reduction of intra- and perivascular ROS may protect against incipient endothelial damage and the CBM thickening that results from such injury.
authors: Department of Anatomy and Cell Biology, University of North Dakota, Grand Forks, ND 58202-9037, USA.
authors: Ana
authors: A
authors: Velic
authors: Donna
authors: D
authors: Laturnus
authors: Jennifer
authors: J
authors: Chhoun
authors: Shirong
authors: S
authors: Zheng
authors: Paul
authors: P
authors: Epstein
authors: Edward
authors: E
authors: Carlson
mesh_terms: D000818:Animals; D001485:Basement Membrane / Q000378:metabolism* / Q000648:ultrastructure; D001786:Blood Glucose / Q000378:metabolism; D002196:Capillaries / Q000378:metabolism* / Q000648:ultrastructure; D003331:Coronary Vessels / Q000378:metabolism* / Q000648:ultrastructure; D058065:Diabetic Cardiomyopathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005838:Genotype; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D008297:Male; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000648:ultrastructure; D018384:Oxidative Stress; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D001786:Blood Glucose; D006442:Glycated Hemoglobin; D008668:Metallothionein; D017382:Reactive Oxygen Species; C491053:MT2A protein, human