Cardiac-specific leptin receptor deletion exacerbates ischaemic heart failure in mice.
OBJECTIVE
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.


RESULTS
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.


CONCLUSIONS
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.
McGaffin
Kenneth R
KR
Cardiovascular Institute, University of Pittsburgh Medical Center, 1750 Bioscience Tower, 200 Lothrop Street, Pittsburgh, PA 15213, USA. mcgaffinkr@upmc.edu
Witham
William G
WG
Yester
Keith A
KA
Romano
Lia C
LC
O'Doherty
Robert M
RM
McTiernan
Charles F
CF
O'Donnell
Christopher P
CP
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D006019:Glycolysis; D006333:Heart Failure / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008955:Models, Cardiovascular; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D012265:Ribonucleotides / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology
D012265:Ribonucleotides; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D013629:Tamoxifen; D000620:Aminoimidazole Carboxamide; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide