Cardiac-specific leptin receptor deletion exacerbates ischaemic heart failure in mice
Open Access
- 9 September 2010
- journal article
- research article
- Published by Oxford University Press (OUP) in Cardiovascular Research
- Vol. 89 (1), 60-71
- https://doi.org/10.1093/cvr/cvq288
Abstract
The obesity-related adipokine, leptin, has multiple actions on peripheral organs, including the mitigation of adverse cardiovascular outcomes after myocardial infarction (MI). Although we recently demonstrated that leptin, its receptor, and downstream signalling are up-regulated in the heart after MI, the significance of intact cardiomyoctye leptin signalling is unknown. Therefore, our objective was to generate a cardiomyocyte-specific leptin receptor knock-out (ObRKO) mouse to determine whether worse cardiac outcomes after MI result from impaired leptin signalling in cardiomyocytes. Tamoxifen-inducible ObRKO mice were subjected to experimental MI or sham surgeries and studied after 1 month. After MI, ObRKO mice displayed a loss of cardiac signal transducer and activator of transcription (STAT) 3 and adenosine monophosphate-activated protein kinase (AMPK) signalling. Worse survival and cardiac morbidity were also seen in the ObRKO mouse post-MI, including decreased contractile function and glycolytic metabolism, and increased left ventricular dilation, hypertrophy, collagen deposition, matrix metalloproteinase activity, apoptosis, and inflammation. Treatment of ObRKO mice post-MI with an ObR-independent AMPK activator improved cardiac function and restored many of these maladaptive processes to wild-type levels. These data indicate that leptin signalling mitigates cardiac injury in the post-MI failing heart by acting directly on cardiomyocytes to increase STAT3 and AMPK activation, to decrease cardiac hypertrophy, apoptosis, and inflammation, and to limit deleterious changes in cardiac structure, function, and glycolytic metabolism.Keywords
This publication has 43 references indexed in Scilit:
- Leptin Signaling in the Failing and Mechanically Unloaded Human HeartCirculation: Heart Failure, 2009
- Chronic intermittent hypoxia increases left ventricular contractility in C57BL/6J miceJournal of Applied Physiology, 2009
- Avoidance of Transient Cardiomyopathy in Cardiomyocyte-Targeted Tamoxifen-Induced MerCreMer Gene Deletion ModelsCirculation Research, 2009
- Extracellular matrix remodeling during the progression of volume overload-induced heart failureJournal of Molecular and Cellular Cardiology, 2009
- AMP-activated protein kinase confers protection against TNF-α-induced cardiac cell deathCardiovascular Research, 2009
- Leptin attenuates cardiac apoptosis after chronic ischaemic injuryCardiovascular Research, 2009
- IL-10 Inhibits Inflammation and Attenuates Left Ventricular Remodeling After Myocardial Infarction via Activation of STAT3 and Suppression of HuRCirculation Research, 2009
- Decreased p110α catalytic activity accompanies increased myocyte apoptosis and cardiac hypertrophy in leptin deficientob/obmiceCell Cycle, 2008
- Ischemia/reperfusion in rat heart induces leptin and leptin receptor gene expressionLife Sciences, 2007
- The Obesity-Associated Peptide Leptin Induces Hypertrophy in Neonatal Rat Ventricular MyocytesCirculation Research, 2003