title: Long-Lived αMUPA Mice Show Attenuation of Cardiac Aging and Leptin-Dependent Cardioprotection.
abstract: αMUPA transgenic mice spontaneously consume less food compared with their wild type (WT) ancestors due to endogenously increased levels of the satiety hormone leptin. αMUPA mice share many benefits with mice under caloric restriction (CR) including an extended life span. To understand mechanisms linked to cardiac aging, we explored the response of αMUPA hearts to ischemic conditions at the age of 6, 18, or 24 months. Mice were subjected to myocardial infarction (MI) in vivo and to ischemia/reperfusion ex vivo. Compared to WT mice, αMUPA showed functional and histological advantages under all experimental conditions. At 24 months, none of the WT mice survived the first ischemic day while αMUPA mice demonstrated 50% survival after 7 ischemic days. Leptin, an adipokine decreasing under CR, was consistently ~60% higher in αMUPA sera at baseline. Leptin levels gradually increased in both genotypes 24h post MI but were doubled in αMUPA. Pretreatment with leptin neutralizing antibodies or with inhibitors of leptin signaling (AG-490 and Wortmannin) abrogated the αMUPA benefits. The antibodies also reduced phosphorylation of the leptin signaling components STAT3 and AKT specifically in the αMUPA myocardium. αMUPA mice did not show elevation in adiponectin, an adipokine previously implicated in CR-induced cardioprotection. WT mice treated for short-term CR exhibited cardioprotection similar to that of αMUPA, however, along with increased adiponectin at baseline. Collectively, the results demonstrate a life-long increased ischemic tolerance in αMUPA mice, indicating the attenuation of cardiac aging. αMUPA cardioprotection is mediated through endogenous leptin, suggesting a protective pathway distinct from that elicited under CR.
authors.affiliation: The Cardiac Research Laboratory, Felsenstein Medical Research Center, Tel Aviv University, Petah Tikva, Israel.
authors.forename: Esther
authors.initials: E
authors.lastname: Levy
authors.affiliation: Cardiology Dept., Rabin Medical Center, Petah Tikva, Israel.
authors.forename: Ran
authors.initials: R
authors.lastname: Kornowski
authors.affiliation: The Cardiac Research Laboratory, Felsenstein Medical Research Center, Tel Aviv University, Petah Tikva, Israel.|Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.
authors.forename: Reut
authors.initials: R
authors.lastname: Gavrieli
authors.affiliation: The Cardiac Research Laboratory, Felsenstein Medical Research Center, Tel Aviv University, Petah Tikva, Israel.|Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.
authors.forename: Ilana
authors.initials: I
authors.lastname: Fratty
authors.affiliation: Cardiology Dept., Rabin Medical Center, Petah Tikva, Israel.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Greenberg
authors.affiliation: The Cardiac Research Laboratory, Felsenstein Medical Research Center, Tel Aviv University, Petah Tikva, Israel.
authors.forename: Maayan
authors.initials: M
authors.lastname: Waldman
authors.affiliation: Cardiology Dept. and Schneider Children's Medical Center, Tel Aviv University, Petah Tikva, Israel.
authors.forename: Einat
authors.initials: E
authors.lastname: Birk
authors.affiliation: Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.
authors.forename: Asher
authors.initials: A
authors.lastname: Shainberg
authors.affiliation: The Cardiac Research Laboratory, Felsenstein Medical Research Center, Tel Aviv University, Petah Tikva, Israel.
authors.forename: Amit
authors.initials: A
authors.lastname: Akirov
authors.affiliation: Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Ruth
authors.initials: R
authors.lastname: Miskin
authors.affiliation: The Cardiac Research Laboratory, Felsenstein Medical Research Center, Tel Aviv University, Petah Tikva, Israel.
authors.forename: Edith
authors.initials: E
authors.lastname: Hochhauser
mesh_terms: D054392:Adipokines / Q000097:blood; D000818:Animals; D015415:Biomarkers; D016922:Cellular Senescence / Q000235:genetics; D004195:Disease Models, Animal; D004452:Echocardiography; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D053208:Kaplan-Meier Estimate; D020738:Leptin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000209:etiology / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020032:Tyrphostins / Q000494:pharmacology; D016276:Ventricular Function
chemical_list: D054392:Adipokines; D015415:Biomarkers; D020738:Leptin; D050796:STAT3 Transcription Factor; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D051057:Proto-Oncogene Proteins c-akt