Cardiac leptin overexpression in the context of acute MI and reperfusion potentiates myocardial remodeling and left ventricular dysfunction

Abstract

BackgroundAcute MI induces leptin expression in the heart, however the role of myocardial leptin in cardiac ischemia and reperfusion (IR) remains unknown. To shed light on the effects of elevated levels of leptin in the myocardium, we overexpressed cardiac leptin and assessed local remodeling and myocardial function in this context.Methods and resultsCardiac leptin overexpression was stimulated in mice undergoing IR by a single intraperitoneal injection of leptin antagonist (LepA). All mice exhibited a normal pattern of body weight gain. A rapid, long-term upregulation of leptin mRNA was demonstrated in the heart, adipose, and liver tissues in IR/LepA-treated mice. Overexpressed cardiac leptin mRNA extended beyond postoperative day (POD) 30. Plasma leptin peaked 7.5 hours postoperatively, especially in IR/LepA-treated mice, subsiding to normal levels by 24 hours. On POD-30 IR/LepA-treated mice demonstrated cardiomyocyte hypertrophy and perivascular fibrosis compared to IR/saline controls. Echocardiography on POD-30 demonstrated eccentric hypertrophy and systolic dysfunction in IR/LepA. We recorded reductions in Ejection Fraction (p<0.001), Fraction Shortening (p<0.01), and Endocardial Fraction Area Change (p<0.01), and an increase in Endocardial Area Change (p<0.01). Myocardial remodeling in the context of IR and cardiac leptin overexpression was associated with increased cardiac TGFβ ligand expression, activated Smad2, and downregulation of STAT3 activity.ConclusionsCardiac IR coinciding with increased myocardial leptin synthesis promotes cardiomyocyte hypertrophy and fibrosis and potentiates myocardial dysfunction. Plasma leptin levels do not reflect cardiac leptin synthesis, and may not predict leptin-related cardiovascular morbidity. Targeting cardiac leptin is a potential treatment for cardiac IR damage.

Cardioprotective properties of leptin in patients with excessive body mass

“…Plasma concentration of leptin corresponds mainly to its synthesis by adipocytes. Recent study on murine model suggests that the hypertrophic action is related to the overexpression of cardiac leptin [ 26 ]. The limitations of available measurement methods make it impossible to determine the concentration of cardiac leptin in samples from patients.…”

Adipokines and Inflammation: Focus on Cardiovascular Diseases

“…Hyperleptinemia is considered an independent risk factor for coronary artery disease (CAD) and a strong predictor of acute myocardial infarction (AMI) [ 47 , 48 ]. In mice with leptin overexpression, cardiac ischemia/reperfusion (I/R) leads to cardiomyocyte hypertrophy and fibrosis and worsens myocardial dysfunction [ 49 ]. Patients with myocardial infarction (MI) have increased circulating levels of leptin, which correlates with pro-inflammatory markers, suggesting that leptin is associated with the inflammatory response produced during an AMI [ 50 , 51 , 52 ].…”

Effect of Leptin on Chronic Inflammatory Disorders: Insights to Therapeutic Target to Prevent Further Cardiovascular Complication

“…164 Therefore, it has autocrine and paracrine effects on the vascular modulation process. 36 Investigations done on animal models showed that leptin leads to the development of atherosclerosis and thrombosis, which act as risk factors for CAD. 27 Even though animal investigations revealed that it contributes to atherosclerosis development, 115 findings from clinical investigations as well as experimental animal studies showed leptin's protective effect against atherosclerosis.…”

“…34 Even if contradictory data has been shown in vascular diseases, 35 hyperleptinemia is the adverse effect of cardiovascular complications such as stroke, heart failure, and acute myocardial infarction. 36 Although scientific evidence had argument on leptin effect in coronary artery disease, it has a correlation with intimamedia thickness and calcification of coronary artery among type II diabetes mellitus patients. 37 Coronary artery disease (CAD) is associated with increased synthesis of the perivascular adipose tissue derived leptin and its atherogenic effect.…”