A neutralizing leptin receptor antibody mitigates hypertrophy and hemodynamic dysfunction in the postinfarcted rat heart

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.

The Small-Molecule Fast Skeletal Troponin Activator, CK-2127107, Improves Exercise Tolerance in a Rat Model of Heart Failure

“…Heart mass, normalized to body mass, was significantly higher in LAD-HF rats than in the sham controls (4.3 6 0.1 versus 3.5 6 0.01 mg heart/g body mass; P , 0.0001; Fig. 2B), which is consistent with the pathologic cardiac hypertrophy that typically occurs in myocardial infarction-induced heart failure (Rubin et al, 1983;Purdham et al, 2008). Masson's trichrome stains of heart sections from sham controls and LAD-HF rats revealed extensive collagen disposition distal to the ligation site in the left ventricle of LAD-HF rats (Supplemental Fig.…”

Ginseng Reverses Established Cardiomyocyte Hypertrophy and Postmyocardial Infarction-Induced Hypertrophy and Heart Failure

“…However, work from our laboratory and that of others has clearly demonstrated marked left ventricular systolic and diastolic dysfunction as early as 1 week after CAL, which is well established at the 4-week period. 9,[18][19][20] We have confirmed this in the present study in rats (N=5) subjected to catheter-based left ventricular function assessment 4 weeks after CAL. These animals demonstrated a 3-fold increase in left ventricular end-diastolic pressure and a 21% reduction in left ventricular end-systolic pressure compared with rats subjected to sham procedure, accompanied by a 43% increase in the left ventricular weight/body weight values (data not shown).…”

Leptin regulates MMP-2, TIMP-1 and collagen synthesis via p38 MAPK in HL-1 murine cardiomyocytes

“…Numerous studies suggest that leptin is an important mediator of pathological cardiac remodeling [13,14,17,19,[21][22][23][24], which is characterized by cardiomyocyte hypertrophy and a disruption of the ECM resulting in increased collagen deposition [1,3]. Here we investigated the effect of leptin on regulation of myocardial matrix components, specifically MMP-2 activity, TIMP-1 expression and collagen-I/-III expression, in HL-1 cardiomyocytes.…”

“…Concentrations of circulating leptin in lean and obese individuals are between 2-10 ng/ml and 10-100 ng/ml, respectively [35]. Leptin, although primarily produced by adipocytes [9], is additionally synthesized by a plethora of tissues [11][12][13][14][15][16][17], including the heart [10]. The cardiac effects of leptin have yet to be fully elucidated, however, leptin regulates cardiomyocyte hypertrophy [13][14][15]19] hyperplasia [13], apoptosis [33] and the production of various myocardial matrix components by cardiomyocytes and cardiac fibroblasts [13,16] The underlying mechanism through which obesity contributes to the development of cardiac fibrosis in cardiovascular disease, however, remains poorly understood.…”