Downregulation of oxytocin and natriuretic peptides in diabetes: possible implications in cardiomyopathy.
Regular physical activity is beneficial in preventing the risk of cardiovascular complications of diabetes. Recent studies showed a cardioprotective role of oxytocin (OT) to induce natriuretic peptides (NPs) and nitric oxide (NO) release. It is not known if the diabetic state is associated with a reduced OT-NPs-NO system and if exercise training improves this system. To address this, we investigated the effects of treadmill running using the db/db mouse model of type 2 diabetes. Eight-week-old db/db mice were subjected to running 5 days per week for a period of 8 weeks. The lean db/+ littermates were used as controls. Sedentary db/db mice were obese and hyperglycaemic, and exercise training was not effective in reducing body weight and the hyperglycaemic state. Compared to control mice, db/db mice had lower heart weight and heart-to-body weight ratios. In these mice, this was associated with augmented cardiac apoptosis, cardiomyocyte enlargement and collagen deposits. In addition, db/db mice displayed significant downregulation in gene expression of OT (76%), OT receptors (65%), atrial NP (ANP; 43%), brain NP (BNP; 87%) and endothelial nitric oxide synthase (eNOS) (54%) in the heart (P < 0.05). Exercise training had no effect on expression of these genes which were stimulated in control mice. In response to exercise training, the significant increment of anti-apoptotic Bcl-2 gene expression was observed only in control mice (P < 0.05). In conclusion, downregulation of the OT-NPs-NO system occurs in the heart of the young db/db mouse. Exercise training was not effective in reversing the defect, suggesting impairment of this cardiac protective system in diabetes.
Gutkowska
Jolanta
J
Laboratory of Cardiovascular Biochemistry, Research Centre, Centre Hospitalier de L'Université de Montréal-Hôtel-Dieu, Montréal, Québec, Canada. jolanta.gutkowska@umontreal.ca
Broderick
Tom L
TL
Bogdan
Danalache
D
Wang
Donghao
D
Lavoie
Jean-Marc
JM
Jankowski
Marek
M
D000818:Animals; D001483:Base Sequence; D009202:Cardiomyopathies / Q000209:etiology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D017931:DNA Primers / Q000235:genetics; D048909:Diabetes Complications / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000235:genetics* / Q000628:therapy; D004195:Disease Models, Animal; D015536:Down-Regulation; D019254:Genes, bcl-2; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D045265:Natriuretic Peptides / Q000235:genetics*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D010121:Oxytocin / Q000235:genetics*; D010805:Physical Conditioning, Animal; D005082:Physical Exertion; D018045:Receptors, Oxytocin / Q000235:genetics; D012307:Risk Factors
D017931:DNA Primers; D045265:Natriuretic Peptides; D018045:Receptors, Oxytocin; D010121:Oxytocin; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse
Proc Natl Acad Sci U S A. 1997 Oct 14;94(21):11704-9
9326674
Am J Physiol. 1997 May;272(5 Pt 2):H2313-9
9176300
Circulation. 2007 May 15;115(19):2540-8
17502589
Circ Res. 2006 Jan 6;98(1):119-24
16339484
Physiol Rev. 2001 Apr;81(2):629-83
11274341
J Am Soc Hypertens. 2008 Sep-Oct;2(5):318-25
20409913
Braz J Med Biol Res. 2004 Apr;37(4):601-6
15064824
J Biol Chem. 2004 Mar 19;279(12):11384-91
14702342
Can J Physiol Pharmacol. 2009 Feb;87(2):137-42
19234577
Hypertension. 2001 Aug;38(2):292-6
11509492
Am J Physiol Heart Circ Physiol. 2007 May;292(5):H2106-18
17122193
J Am Coll Cardiol. 2006 May 2;47(9):1835-9
16682309
Am J Physiol Heart Circ Physiol. 2000 Jul;279(1):H210-5
10899058
J Biol Chem. 1997 Dec 19;272(51):31937-40
9405382
Lancet. 1997 Jul;350 Suppl 1:SI20-3
9250279
Am J Physiol Endocrinol Metab. 2008 Jun;294(6):E1119-26
18413674
J Biol Chem. 2007 Jul 27;282(30):21945-52
17525155
J Investig Med. 2001 Jul;49(4):310-8
11478406
Pathophysiology. 2008 Oct;15(3):173-9
18653321
Am J Physiol Regul Integr Comp Physiol. 2004 Jul;287(1):R87-96
15044184
Cell. 1996 Feb 9;84(3):491-5
8608603
Regul Pept. 2007 Mar 1;139(1-3):96-101
17140677
Appl Physiol Nutr Metab. 2007 Aug;32(4):711-20
17622286
J Clin Endocrinol Metab. 1997 Sep;82(9):2771-6
9284693
JAMA. 2001 Sep 12;286(10):1218-27
11559268
Hum Mol Genet. 2007 Jun 1;16(11):1343-50
17412758
Circulation. 2006 Apr 4;113(13):1708-14
16585403
Regul Pept. 2008 Nov 29;151(1-3):71-4
18555543
Trends Endocrinol Metab. 2008 May-Jun;19(4):130-7
18337116
Acta Physiol (Oxf). 2008 Jan;192(1):127-35
18171435
Circ Res. 2006 Mar 31;98(6):837-45
16514068
J Am Coll Cardiol. 2004 May 5;43(9):1590-5
15120816
Metabolism. 2001 Sep;50(9):1049-53
11555837
Hypertension. 2009 Feb;53(2):387-92
19029483
N Engl J Med. 2001 May 3;344(18):1343-50
11333990
Hypertension. 2002 Jul;40(1):54-60
12105138
Stem Cells. 2007 Mar;25(3):679-88
17138963
Cell Tissue Res. 1992 Feb;267(2):267-72
1534717
Proc Natl Acad Sci U S A. 2004 Aug 31;101(35):13074-9
15316117
Physiol Genomics. 2005 Mar 21;21(1):34-42
15623566
J Clin Invest. 2003 May;111(10):1497-504
12750399
Am J Physiol Regul Integr Comp Physiol. 2007 Jul;293(1):R267-75
17475680
Psychosom Med. 2005 Jul-Aug;67(4):531-8
16046364
Eur J Pharmacol. 2007 Jul 30;568(1-3):83-8
17537429
Diabetologia. 2008 Jul;51(7):1327-37
18437348
J Appl Physiol Respir Environ Exerc Physiol. 1983 Dec;55(6):1660-4
6363362
Endocrinology. 2005 Dec;146(12):5341-9
16141388
Clin Exp Pharmacol Physiol. 2004 Nov;31(11):791-4
15566395