title: Interaction between age and obesity on cardiomyocyte contractile function: role of leptin and stress signaling.
abstract: OBJECTIVE
  This study was designed to evaluate the interaction between aging and obesity on cardiac contractile and intracellular Ca2+ properties.
  
  
  METHODS
  Cardiomyocytes from young (4-mo) and aging (12- and 18-mo) male lean and the leptin deficient ob/ob obese mice were treated with leptin (0.5, 1.0 and 50 nM) for 4 hrs in vitro. High fat diet (45% calorie from fat) and the leptin receptor mutant db/db obesity models at young and older age were used for comparison. Cardiomyocyte contractile and intracellular Ca2+ properties were evaluated including peak shortening (PS), maximal velocity of shortening/relengthening (+/- dL/dt), time-to-PS (TPS), time-to-90% relengthening (TR(90)), intracellular Ca2+ levels and decay. O2(-) levels were measured by dihydroethidium fluorescence.
  
  
  RESULTS
  Our results revealed reduced survival in ob/ob mice. Aging and obesity reduced PS, +/- dL/dt, intracellular Ca2+ rise, prolonged TR(90) and intracellular Ca2+ decay, enhanced O2(-) production and p(47phox) expression without an additive effect of the two, with the exception of intracellular Ca2+ rise. Western blot analysis exhibited reduced Ob-R expression and STAT-3 phosphorylation in both young and aging ob/ob mice, which was restored by leptin. Aging and obesity reduced phosphorylation of Akt, eNOS and p38 while promoting pJNK and pIkappaB. Low levels of leptin reconciled contractile, intracellular Ca2+ and cell signaling defects as well as O2(-) production and p(47phox) upregulation in young but not aging ob/ob mice. High level of leptin (50 nM) compromised contractile and intracellular Ca2+ response as well as O2(-) production and stress signaling in all groups. High fat diet-induced and db/db obesity displayed somewhat comparable aging-induced mechanical but not leptin response.
  
  
  CONCLUSIONS
  Taken together, our data suggest that aging and obesity compromise cardiac contractile function possibly via phosphorylation of Akt, eNOS and stress signaling-associated O2(-) release.
authors.affiliation: Department of Physiology, Fourth Military Medical University, Xi'an, China. jren@uwyo.edu
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
authors.forename: Feng
authors.initials: F
authors.lastname: Dong
authors.forename: Guo-Jun
authors.initials: GJ
authors.lastname: Cai
authors.forename: Peng
authors.initials: P
authors.lastname: Zhao
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Nunn
authors.forename: Loren E
authors.initials: LE
authors.lastname: Wold
authors.forename: Jianming
authors.initials: J
authors.lastname: Pei
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D020013:Calcium Signaling / Q000502:physiology; D002478:Cells, Cultured; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology; D020738:Leptin / Q000172:deficiency / Q000502:physiology*; D008297:Male; D051379:Mice; D008820:Mice, Obese; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009765:Obesity / Q000503:physiopathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013312:Stress, Physiological; D013481:Superoxides / Q000378:metabolism
chemical_list: D004041:Dietary Fats; D020738:Leptin; D013481:Superoxides; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt
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