title: Ca2+ regulatory mechanisms of exercise protection against coronary artery disease in metabolic syndrome and diabetes.
abstract: Chronic exercise attenuates coronary artery disease (CAD) in humans largely independent of reductions in risk factors; thus major protective mechanisms of exercise are directly within the coronary vasculature. Further, tight control of diabetes, e.g., blood glucose, can be detrimental. Accordingly, knowledge of mechanisms by which exercise attenuates diabetic CAD could catalyze development of molecular therapies. Exercise attenuates CAD (atherosclerosis) and restenosis in miniature swine models, which enable precise control of exercise parameters (intensity, duration, and frequency) and characterization of the metabolic syndrome (MetS) and diabetic milieu. Intracellular Ca(2+) is a pivotal second messenger for coronary smooth muscle (CSM) excitation-contraction and excitation-transcription coupling that modulates CSM proliferation, migration, and calcification. CSM of diabetic dyslipidemic Yucatan swine have impaired Ca(2+) extrusion via the plasmalemma Ca(2+) ATPase (PMCA), downregulation of L-type voltage-gated Ca(2+) channels (VGCC), increased Ca(2+) sequestration by the sarcoplasmic reticulum (SR) Ca(2+) ATPase (SERCA), increased nuclear Ca(2+) localization, and greater activation of K channels by Ca(2+) release from the SR. Endurance exercise training prevents Ca(2+) transport changes with virtually no effect on the diabetic milieu (glucose, lipids). In MetS Ossabaw swine transient receptor potential canonical (TRPC) channels are upregulated and exercise training reverses expression and TRPC-mediated Ca(2+) influx with almost no change in the MetS milieu. Overall, exercise effects on Ca(2+) signaling modulate CSM phenotype. Future studies should 1) selectively target key Ca(2+) transporters to determine definitively their causal role in atherosclerosis and 2) combine mechanistic studies with clinical outcomes, e.g., reduction of myocardial infarction.
authors: Department of Cellular and Integrative Physiology, Indiana University School of Medicine, 635 Barnhill Dr., MS 385, Indianapolis, IN 46202-5120, USA. msturek@iupui.edu
authors: Michael
authors: M
authors: Sturek
references: Cardiovasc Res. 2010 Feb 1;85(3):631-40
references: 19744946
references: Toxicol Pathol. 2006;34(1):11-8
references: 16507539
references: Circulation. 2004 Mar 23;109(11):1371-8
references: 15007010
references: Arterioscler Thromb Vasc Biol. 2008 Jun;28(6):1084-9
references: 18309114
references: Trends Pharmacol Sci. 1995 Mar;16(3):98-105
references: 7792935
references: Circulation. 2003 Mar 18;107(10):1448-53
references: 12642369
references: Am J Physiol. 1995 Oct;269(4 Pt 2):H1246-57
references: 7485555
references: N Engl J Med. 1993 Sep 30;329(14):977-86
references: 8366922
references: Nature. 2008 Feb 21;451(7181):904-13
references: 18288179
references: Am J Physiol Heart Circ Physiol. 2008 Jun;294(6):H2489-96
references: 18390821
references: J Appl Physiol (1985). 2004 Jun;96(6):2240-8
references: 14752123
references: N Engl J Med. 2011 Mar 3;364(9):818-28
references: 21366473
references: Mol Pharmacol. 2004 Nov;66(5):1265-74
references: 15280443
references: Circulation. 2005 Nov 15;112(20):3066-72
references: 16275870
references: Ann N Y Acad Sci. 2002 Nov;976:335-7
references: 12502576
references: Am J Physiol Heart Circ Physiol. 2009 Nov;297(5):H1629-37
references: 19749164
references: Diabetes Care. 2010 Dec;33(12):2692-6
references: 21115771
references: J Physiol. 1992;451:49-78
references: 1403820
references: News Physiol Sci. 2004 Apr;19:44-50
references: 15016901
references: Coron Artery Dis. 2008 Jun;19(4):217-26
references: 18480664
references: Arterioscler Thromb Vasc Biol. 2006 Jul;26(7):1558-65
references: 16690872
references: J Appl Physiol (1985). 2009 Sep;107(3):937-45
references: 19556453
references: Circulation. 2009 May 12;119(18):2531-4
references: 19433770
references: Comp Med. 2006 Feb;56(1):35-45
references: 16521858
references: Am J Physiol Heart Circ Physiol. 2010 Apr;298(4):H1182-9
references: 20118408
references: Atherosclerosis. 2007 Dec;195(2):287-96
references: 17289052
references: Obes Surg. 2007 Oct;17(10):1332-9
references: 18098400
references: Diabetes. 1982;31(Suppl 1 Pt 2):30-6
references: 6761193
references: ILAR J. 2004;45(3):303-13
references: 15229377
references: Ann N Y Acad Sci. 2002 Jun;967:414-23
references: 12079869
references: Circulation. 1992 Jul;86(1):1-11
references: 1617762
references: Diabetologia. 2005 Sep;48(9):1684-99
references: 16079964
references: Diabetes Care. 2005 Jul;28(7):1769-78
references: 15983333
references: Proc R Soc Med. 1965 May;58:295-300
references: 14283879
references: Atherosclerosis. 2003 Mar;167(1):15-23
references: 12618264
references: ILAR J. 2006;47(3):243-58
references: 16804199
references: Am J Physiol Heart Circ Physiol. 2007 Oct;293(4):H2009-23
references: 17586614
references: Circulation. 2003 Apr 29;107(16):2072-5
references: 12719287
references: Physiol Rev. 2004 Jul;84(3):767-801
references: 15269336
references: Pancreas. 2011 Apr;40(3):438-43
references: 21240032
references: Atherosclerosis. 1972 Jan-Feb;15(1):107-22
references: 5062500
references: Atherosclerosis. 1994 Oct;110 Suppl:S27-33
references: 7857380
references: Arterioscler Thromb Vasc Biol. 2009 Sep;29(9):1342-8
references: 19520975
references: J Appl Physiol (1985). 2004 Mar;96(3):1069-79
references: 14634027
references: Circ Res. 2003 Oct 31;93(9):839-47
references: 14551243
references: Am J Physiol Endocrinol Metab. 2011 May;300(5):E848-57
references: 21304063
references: Circ Res. 2002 May 31;90(10):1114-21
references: 12039802
references: J Pharmacol Exp Ther. 2003 Jul;306(1):132-40
references: 12663685
references: J Vasc Interv Radiol. 2010 Oct;21(10):1555-64
references: 20813544
references: Circ Res. 2004 Aug 20;95(4):406-14
references: 15256479
references: Atherosclerosis. 2001 Nov;159(1):117-24
references: 11689213
references: Circ Res. 2007 May 25;100(10):1415-27
references: 17525381
references: Med Sci Sports Exerc. 1994 Oct;26(10):1230-8
references: 7799766
references: J Lipid Res. 2002 Oct;43(10):1618-29
references: 12364546
references: Am J Physiol Heart Circ Physiol. 2010 Mar;298(3):H966-73
references: 20044440
references: Am J Physiol Endocrinol Metab. 2005 Feb;288(2):E412-21
references: 15479954
references: Comp Med. 2003 Feb;53(1):53-64
references: 12625507
references: Microcirculation. 2010 Jan;17(1):3-20
references: 20141596
references: Artery. 1989;16(2):105-17
references: 2712708
references: Circulation. 2006 Nov 28;114(22):2390-411
references: 17130356
references: J Vasc Res. 2001 Sep-Oct;38(5):432-43
references: 11561145
references: Am J Physiol Heart Circ Physiol. 2006 Nov;291(5):H2493-503
references: 16798818
references: J Am Soc Nephrol. 2009 Jul;20(7):1453-64
references: 19478096
references: Science. 2002 Feb 8;295(5557):1089-92
references: 11778012
references: Science. 1995 Oct 27;270(5236):633-7
references: 7570021
references: J Am Coll Cardiol. 2008 Jul 22;52(4):255-62
references: 18634979
references: Arterioscler Thromb Vasc Biol. 1999 Dec;19(12):2981-92
references: 10591679
references: Diabetes Obes Metab. 2007 Nov;9 Suppl 2:170-9
references: 17919191
references: Circ Res. 2006 Mar 3;98(4):557-63
references: 16439693
references: Comp Med. 2005 Oct;55(5):445-51
references: 16270901
references: Circulation. 2007 Nov 6;116(19):2110-8
references: 17967770
references: Arterioscler Thromb Vasc Biol. 2007 Apr;27(4):799-805
references: 17234727
references: JAMA. 2006 Apr 5;295(13):1556-65
references: 16533939
references: Diabetes Metab Syndr Obes. 2011;4:99-105
references: 21660293
references: Obes Rev. 2010 Nov;11(11):792-807
references: 19845867
references: J Appl Physiol (1985). 2009 Jan;106(1):1-2
references: 18948441
references: J Appl Physiol (1985). 2003 Sep;95(3):1301-4
references: 12754176
references: J Lipid Res. 2009 Apr;50 Suppl:S172-7
references: 19020338
references: Circ Res. 1992 Oct;71(4):1008-14
references: 1325295
references: Hypertension. 2003 Mar;41(3 Pt 2):625-33
references: 12623970
references: J Pharmacol Exp Ther. 2010 Dec;335(3):781-7
references: 20855445
references: Arterioscler Thromb Vasc Biol. 2010 Sep;30(9):1711-7
references: 20576943
references: J Appl Physiol (1985). 2006 Sep;101(3):752-62
references: 16763107
references: Circulation. 2004 Jan 27;109(3):433-8
references: 14744958
references: Circulation. 2006 Jun 27;113(25):2943-6
references: 16801475
references: Comp Med. 2001 Apr;51(2):150-5
references: 11922179
references: Comp Med. 2007 Oct;57(5):493-504
references: 17974133
references: Diabetologia. 2000 May;43(5):632-41
references: 10855538
references: Proteomics. 2009 May;9(9):2468-83
references: 19402046
references: Circ Res. 2008 Oct 10;103(8):e97-104
references: 18802022
references: Arterioscler Thromb Vasc Biol. 2006 Aug;26(8):1693-701
references: 16763160
references: J Appl Physiol (1985). 2003 Sep;95(3):1179-93
references: 12777409
references: Am J Physiol Gastrointest Liver Physiol. 2010 May;298(5):G746-54
references: 20167877
references: Hepatology. 2009 Jul;50(1):56-67
references: 19434740
references: J Physiol. 1992;451:25-48
references: 1403813
references: Am J Physiol. 1990 Aug;259(2 Pt 2):H643-7
references: 2386234
references: Circulation. 1993 Apr;87(4):1076-82
references: 8462135
references: Am J Physiol Heart Circ Physiol. 2002 Dec;283(6):H2397-410
references: 12388302
references: Biomaterials. 2011 Apr;32(10):2516-23
references: 21216002
references: Diabetes. 1996 Jul;45(7):876-80
references: 8666136
references: J Biomed Opt. 2011 Feb;16(2):021110
references: 21361673
references: Coron Artery Dis. 2008 Feb;19(1):27-31
references: 18281812
references: Circulation. 2007 Jan 23;115(3):326-32
references: 17210840
references: Med Sci Sports Exerc. 2005 Jul;37(7):1119-25
references: 16015127
references: Metabolism. 2004 Aug;53(8):1021-6
references: 15281012
references: Comp Med. 2002 Dec;52(6):523-9
references: 12540165
references: Am J Physiol Heart Circ Physiol. 2009 Nov;297(5):H1580-2
references: 19749161
references: Arterioscler Thromb Vasc Biol. 2004 Jul;24(7):1266-71
references: 15142859
references: Coron Artery Dis. 2006 May;17(3):219-25
references: 16728870
references: Acta Physiol Scand. 2003 Jun;178(2):117-21
references: 12780385
references: Nature. 2003 Jun 5;423(6940):599-602
references: 12789325
references: Am J Physiol Endocrinol Metab. 2006 Apr;290(4):E670-7
references: 16278249
references: Comp Med. 2003 Feb;53(1):42-52
references: 12625506
references: Am J Physiol Heart Circ Physiol. 2005 Mar;288(3):H1233-41
references: 15528227
references: Exp Biol Med (Maywood). 2009 Jun;234(6):683-92
references: 19307464
references: Comp Med. 2008 Apr;58(2):168-73
references: 18524175
references: J Am Coll Cardiol. 2001 Jun 1;37(7):1891-900
references: 11401128
references: Diabetes. 2001 Jul;50(7):1654-65
references: 11423488
references: Heart. 2004 Jul;90(7):732-8
references: 15201238
references: Circulation. 2002 Nov 26;106(22):2760-3
references: 12450998
references: Circ Res. 2006 Apr 14;98(7):868-78
references: 16614312
references: J Biomed Opt. 2007 Sep-Oct;12(5):054007
references: 17994895
references: J Vasc Res. 2002 May-Jun;39(3):208-20
references: 12097819
references: N Engl J Med. 1981 Dec 17;305(25):1483-9
references: 7300873
references: J Appl Physiol (1985). 2010 Jun;108(6):1766-74
references: 20299615
references: Comp Med. 2010 Aug;60(4):300-15
references: 20819380
references: Diabetes Care. 2004 Oct;27(10):2444-9
references: 15451914