Cardiovascular Research Advance Access first published online on September 10, 2009
This version [Corrected Proof] published online on October 4, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp308
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Exercise training decreases store-operated Ca2+entry associated with metabolic syndrome and coronary atherosclerosis
1 Department of Cellular and Integrative Physiology, Indiana University School of Medicine, 635 Barnhill Drive, MS 385, Indianapolis, IN 46202-5120, USA
2 Department of Integrative Medical Sciences, Northeastern Ohio Universities Colleges of Medicine, OH, USA
* Corresponding author. Tel: +1 317 274 7772, Fax: +1 317 274 3318, Email: msturek{at}iupui.edu
Aims: Stenting attenuates restenosis, but accelerated coronary artery disease (CAD) adjacent to the stent (peri-stent CAD) remains a concern in metabolic syndrome (MetS). Smooth muscle cell proliferation, a major mechanism of CAD, is mediated partly by myoplasmic Ca2+ dysregulation and store-operated Ca2+ entry (SOCE) via canonical transient receptor potential 1 (TRPC1) channels is proposed to play a key role. Exercise is known to prevent Ca2+ dysregulation in CAD. We tested the hypothesis that MetS increases SOCE and peri-stent CAD and exercise attenuates these events.
Methods and results: Groups (n = 9 pigs each) were (i) healthy lean Ossabaw swine fed standard chow, (ii) excess calorie atherogenic diet fed (MetS), and (iii) aerobically exercise trained starting after 50 weeks of development of MetS (XMetS). Bare metal stents were placed after 54 weeks on diets, and CAD and SOCE were assessed 4 weeks later. Coronary cells were dispersed proximal to the stent (peri-stent) and from non-stent segments, and fura-2 fluorescence was used to assess SOCE, which was verified by Ni2+ blockade and insensitivity to nifedipine. XMetS pigs had increased physical work capacity and decreased LDL/HDL (P < 0.05), but no attenuation of robust insulin resistance, glucose intolerance, hypertriglyceridaemia, or hypertension. CAD was greater in peri-stented vs. non-stented artery segments. MetS had the greatest CAD, SOCE, and TRPC1 and STIM1 mRNA and protein expression, which were all attenuated in XMetS.
Conclusion: This is the first report of the protective effect of exercise on native CAD, peri-stent CAD, SOCE, and molecular expression of TRPC1, STIM1, and Orai1 in MetS.
KEYWORDS Transient receptor potential 1 channel; STIM1; Orai1; Store-operated calcium channel; Intravascular ultrasound; Coronary smooth muscle; Ossabaw miniature swine
Time for primary review: 21 days
These authors contributed equally to this work.