Homocysteine enriched diet leads to prolonged QT interval and reduced left ventricular performance in telemetric monitored mice.
OBJECTIVE
Homocysteine (Hcy) is a sulfur-containing, non-protein amino acid produced in the metabolic pathway of methionine. Hyperhomocysteinemia is associated with cerebro- and cardiovascular disease in industrialized countries, mostly resulting from protein rich diet and sedentary life style. Matrix metalloproteinases are involved in cardiac remodeling, leading to degradation of intercellular junctions, cardiac connexins and basement membranes. The study was designed to investigate the relationship between Hcy, cardiac remodeling, cardiac performance, and rhythm disturbances in an animal model of hyperhomocysteinemia. We tested the hypothesis that induction of matrix metalloproteinase-2 and matrix metalloproteinase-9 leads to connexin 40, connexin 43, connexin 45 expression changes contributing to decreased cardiac performance and disturbed atrioventricular conduction.


RESULTS
Hcy was added to drinking water of male C57/BL6J mice to achieve moderate Hcy blood levels. ECG was monitored in conscious mice with a telemetric ECG device; echocardiography was used for assessment of left ventricular function. Immunoblotting was used to evaluate matrix metalloproteinase-2, matrix metalloproteinase-9, connexin 40, connexin 43, and connexin 45 expression in cardiac tissue. Animals fed Hcy showed significant prolongation of QRS, QTc, and PR intervals along with reduced left ventricular function. Western blotting showed increased expression of matrix metalloproteinase-2, matrix metalloproteinase-9 and decreased expression of connexin 40, 43, and 45.


CONCLUSIONS
Hcy has been identified as a nutritional factor contributing to cardiovascular disease. Cardiac remodeling induced by matrix metalloproteinase-2 and matrix metalloproteinase-9 and decreased expression of connexin 40, 43, and 45 appears to play a role in the pathomechanism of atrioventricular conduction delay and ventricular dilatation in hyperhomocysteinemia.
Department of Physiology and Biophysics, School of Medicine, 500 S. Preston St, University of Louisville, Louisville, KY 40202, USA. dorothea.rosenberger@louisville.edu
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D
Rosenberger
R
R
Gargoum
N
N
Tyagi
N
N
Metreveli
U
U
Sen
C
C
Maldonado
S
S
Tyagi
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology*; D002318:Cardiovascular Diseases / Q000209:etiology; D017630:Connexins / Q000378:metabolism; D004032:Diet / Q000009:adverse effects; D004195:Disease Models, Animal; D004452:Echocardiography; D006352:Heart Ventricles / Q000378:metabolism / Q000503:physiopathology; D006710:Homocysteine / Q000009:adverse effects* / Q000097:blood; D020138:Hyperhomocysteinemia / Q000097:blood / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009431:Neural Conduction; D011897:Random Allocation; D013686:Telemetry; D018487:Ventricular Dysfunction, Left / Q000209:etiology*; D020257:Ventricular Remodeling
D017630:Connexins; D006710:Homocysteine; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse