Interaction between age and obesity on cardiomyocyte contractile function: role of leptin and stress signaling.
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.
Ren
Jun
J
Department of Physiology, Fourth Military Medical University, Xi'an, China. jren@uwyo.edu
Dong
Feng
F
Cai
Guo-Jun
GJ
Zhao
Peng
P
Nunn
Jennifer M
JM
Wold
Loren E
LE
Pei
Jianming
J
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
D004041:Dietary Fats; D020738:Leptin; D013481:Superoxides; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt
Curr Pharm Des. 2009;15(1):110-7
19149606
Obesity (Silver Spring). 2006 Jul;14 Suppl 4:156S-159S
16931498
Obesity (Silver Spring). 2007 Nov;15(11):2699-711
18070761
Gen Physiol Biophys. 2008 Sep;27(3):152-8
18981529
Acta Clin Belg. 2009 Jan-Feb;64(1):23-34
19317238
Diabetologia. 2006 Jun;49(6):1421-33
16586065
Diabetes. 2005 Apr;54(4):1157-63
15793256
Hypertension. 2002 Jan;39(1):69-74
11799081
Obesity (Silver Spring). 2009 Jun;17(6):1114-23
19214173
Circulation. 2003 Aug 12;108(6):754-9
12885755
Curr Opin Clin Nutr Metab Care. 2008 May;11(3):303-8
18403928
Int J Obes (Lond). 2008 Dec;32(12):1873-4
18982010
J Hypertens. 2006 Mar;24(3):549-61
16467659
Chem Rev. 2004 Mar;104(3):1255-82
15008623
J Nutr. 1987 Feb;117(2):376-82
3559752
J Physiol. 2005 Jun 1;565(Pt 2):463-74
15760936
Diabetologia. 2005 Nov;48(11):2412-21
16172869
Cell Cycle. 2003 May-Jun;2(3):220-3
12734428
Circ Res. 2006 Jan 6;98(1):119-24
16339484
Diabetologia. 2006 Jun;49(6):1434-46
16612592
Clin Chem. 1998 Aug;44(8 Pt 2):1821-5
9702991
Dig Dis Sci. 2008 Apr;53(4):1084-7
17939045
Curr Hypertens Rep. 2008 Dec;10(6):448-53
18959830
J Endocrinol. 2004 Apr;181(1):1-10
15072562
Hypertension. 2000 Oct;36(4):501-5
11040226
Int J Obes Relat Metab Disord. 1999 Jan;23(1):75-82
10094581
Am J Physiol Regul Integr Comp Physiol. 2003 Apr;284(4):R1037-42
12521924
Cardiovasc Res. 2006 Oct 1;72(1):101-11
16901475
Diabetes. 2007 Sep;56(9):2201-12
17575086
Am J Physiol Endocrinol Metab. 2003 Feb;284(2):E366-76
12531745
Respir Physiol Neurobiol. 2009 May 30;167(1):87-100
19450766
Cardiovasc Res. 2006 Jul 15;71(2):208-15
16631149
Pharmacol Ther. 2008 Sep;119(3):291-310
18606183
Nat Rev Cardiol. 2010 Jan;7(1):22-9
19949425
Hypertension. 2006 Feb;47(2):222-9
16380530
Hypertension. 2000 Apr;35(4):1009-15
10775577
Circulation. 2002 Jun 18;105(24):2923-8
12070124
J Gerontol A Biol Sci Med Sci. 2001 Oct;56 Spec No 2:47-53
11730237
FASEB J. 2006 May;20(7):1024-6
16585059
Circulation. 2004 Sep 7;110(10):1269-75
15313952
Obes Rev. 2008 Mar;9(2):165-80
18257754
Am J Physiol Heart Circ Physiol. 2003 Feb;284(2):H464-74
12414444
Nature. 2002 Nov 21;420(6913):333-6
12447443
Am J Physiol Heart Circ Physiol. 2000 Oct;279(4):H1708-14
11009458
J Endocrinol. 2006 Jan;188(1):25-36
16394172
J Am Coll Cardiol. 2009 Jan 13;53(2):167-75
19130985
Biol Pharm Bull. 2005 Aug;28(8):1514-6
16079504