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A neutralizing leptin receptor antibody mitigates hypertrophy and hemodynamic dysfunction in the postinfarcted rat
Daniel M Purdham1, Venkatesh Rajapurohitam, Asad Zeidan
1Dept. of Physiology and Pharmacology, Univ. of Western Ontario, London, ON, N6A 5C1, Canada.
Insights
Leptin receptor blockade improved cardiac function and reduced hypertrophy after coronary artery ligation (CAL) in rats. This suggests endogenous leptin contributes to post-infarction heart remodeling.
Area of Science:
- Cardiology
- Endocrinology
- Molecular Biology
Background:
- Leptin, an adipokine, has known hypertrophic effects on cardiomyocytes in vitro.
- The role of endogenous leptin in post-infarction cardiac remodeling and heart failure remains unclear.
Purpose of the Study:
- To investigate the effect of leptin receptor blockade in vivo on cardiac hypertrophy and hemodynamic function following coronary artery ligation (CAL).
Main Methods:
- Rats underwent left main coronary artery ligation (CAL) or sham operation.
- Leptin receptor antibody was administered to block receptor activity.
- Cardiac function, hypertrophy markers (left ventricular weight-to-body weight ratio, atrial natriuretic peptide gene expression), and extracellular matrix remodeling genes were assessed at 7 and 28 days post-CAL.
Main Results:
- Coronary artery ligation (CAL) induced significant myocardial hypertrophy, evident by increased left ventricular weight-to-body weight ratio and atrial natriuretic peptide gene expression.
- Leptin receptor antagonism abrogated CAL-induced hypertrophy and significantly improved left ventricular systolic function.
- Leptin receptor blockade attenuated increased left ventricular end-diastolic pressure and reduced the expression of genes involved in extracellular matrix remodeling 28 days post-CAL.
Conclusions:
- Endogenous leptin contributes to cardiac hypertrophy following coronary artery ligation (CAL).
- Targeting the myocardial leptin receptor with neutralizing antibodies may represent a novel therapeutic strategy for attenuating post-infarction cardiac remodeling and heart failure.
Abstract:
The 16 kDa adipokine leptin has been shown to exert direct hypertrophic effects on cultured cardiomyocytes although its role as an endogenous contributor to postinfarction remodeling and heart failure has not been determined. We therefore investigated the effect of leptin receptor blockade in vivo on hemodynamic function and cardiac hypertrophy following coronary artery ligation (CAL). Cardiac function and biochemical parameters were measured in rats subjected to 7 or 28 days of left main CAL in the presence and absence of a leptin receptor antibody. Animals subjected to an identical treatment in which the artery was not tied served as sham-operated controls. CAL produced myocardial hypertrophy, which was most pronounced 28 days postinfarction as demonstrated by increases in both left ventricular weight-to-body weight ratio and atrial natriuretic peptide gene expression, both of which were abrogated by leptin receptor antagonism. Leptin receptor blockade also significantly improved left ventricular systolic function, attenuated the increased left ventricular end-diastolic pressure, and reduced the expression of genes associated with extracellular matrix remodeling 28 days following CAL. In conclusion, the ability of a leptin receptor-neutralizing antibody to improve cardiac function offers evidence that endogenous leptin contributes to cardiac hypertrophy following CAL. The possibility exists that targeting the myocardial leptin receptor represents a viable and novel approach toward attenuating postinfarction remodeling.
