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Blockage of receptor for advanced glycation end products prevents development of cardiac dysfunction in db/db type 2 diabetic mice
Author(s) -
Nielsen Jan M.,
Kristiansen Steen B.,
Nørregaard Rikke,
Andersen Claus L.,
Denner Larry,
Nielsen Torsten T.,
Flyvbjerg Allan,
Bøtker Hans E.
Publication year - 2009
Publication title -
european journal of heart failure
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.149
H-Index - 133
eISSN - 1879-0844
pISSN - 1388-9842
DOI - 10.1093/eurjhf/hfp070
Subject(s) - medicine , glycation , preload , cardiac function curve , endocrinology , rage (emotion) , diabetic cardiomyopathy , receptor , cardiology , diastole , diabetes mellitus , heart failure , cardiomyopathy , biology , hemodynamics , blood pressure , neuroscience
Aims Activation of the receptor for advanced glycation end products (RAGE) is associated with long‐term complications in diabetes mellitus. In this study, we tested whether RAGE activation in the diabetic myocardium is implicated in the development of cardiac dysfunction. Methods and results Using MRI and conductance catheter techniques, we evaluated cardiac function in a type 2 diabetic mouse model (db/db), and assessed the effect of blocking RAGE with a RAGE antibody. Gene expressions were evaluated in samples of myocardial tissue. Diabetic db/db mice demonstrated an accelerated age‐dependent deterioration in cardiac function associated with altered expression of genes related to cardiac structure and function. Blockage of RAGE signalling prevented the reduction in systolic function (preload recruitable stroke work: 109.8 ± 13.8 vs. 94.5 ± 14.9 mmHg/µL, P = 0.04) and development of increased LV diastolic chamber stiffness (0.18 ± 0.05 vs. 0.27 ± 0.07 mmHg, P = 0.01). The cardiac expression of collagen (col1a1) was reduced by approximately 45% and the expression of myosin was switched from the foetal isoform (MHCβ) to the adult isoform (MHCα). Conclusion Activation of RAGE is a significant pathogenetic mechanism for the development of cardiac dysfunction in type 2 diabetes. The underlying mechanisms involve not only the passive biophysical properties of the myocardium but also myocyte function.