Exercise training attenuates coronary smooth muscle phenotypic modulation and nuclear Ca²⁺ signaling

Abstract

Exercise training attenuates coronary smooth muscle phenotypic modulation and nuclear Ca 2ϩ signaling. Am J Physiol Heart Circ Physiol 283: H2397-H2410, 2002. First published July 26. 2002 10.1152/ajpheart.00371. 2001.-Physical inactivity is an independent risk factor for coronary heart disease, yet the mechanism(s) of exerciserelated cardioprotection remains unknown. We tested the hypothesis that coronary smooth muscle after exercise training would have decreased mitogen-induced phenotypic modulation and enhanced regulation of nuclear Ca 2ϩ . Yucatan swine were endurance exercise trained (EX) on a treadmill for 16-20 wk. EX reduced endothelin-1-induced DNA content by 40% compared with sedentary (SED) swine (P Ͻ 0.01). EX decreased single cell peak endothelin-1-induced cytosolic Ca 2ϩ responses compared with SED by 16% and peak nuclear Ca 2ϩ responses by 33% (P Ͻ 0.05), as determined by confocal microscopy. On the basis of these results, we hypothesized that sarco(endo)plasmic reticulum Ca 2ϩ -ATPase (SERCA) and intracellular Ca 2ϩ stores in native smooth muscle are spatially localized to dissociate cytosolic Ca 2ϩ and nuclear Ca 2ϩ . Subcellular localization of SERCA in living and fixed cells revealed a distribution of SERCA near the sarcolemma and on the nuclear envelope. These results show that EX enhances nuclear Ca 2ϩ regulation, possibly via SERCA, which may be one mechanism by which coronary smooth muscle cells from EX are less responsive to mitogeninduced phenotypic modulation.endothelin-1; sarco(endo)plasmic reticulum Ca 2ϩ -ATPase; electron microscopy; fluorescence microscopy; swine SUBSTANTIAL EVIDENCE EXISTS supporting the role of chronic endurance exercise training in reducing the incidence of coronary heart disease (6, 39), yet the mechanism(s) of exercise-related cardioprotection remains unknown. Coronary heart disease can be subdivided into two general categories: diseases of coronary vessel tone, i.e., acute vasospasm and hypertension, and diseases of vessel injury, i.e., atherosclerosis. Several studies from our laboratory have addressed mechanisms associated with exercise training adaptations (for reviews, see Refs. 10 and 43). However, there are few studies (48) addressing exercise-related coronary smooth muscle adaptations and their relationship to resistance to the development of vascular disease.Atherosclerosis is a complex disease involving an inflammatory-fibroproliferative response that develops from various forms of insult to the endothelium and smooth muscle cells of the artery (38). The phenotypic modulation of smooth muscle cells plays a key role in the development of atherosclerosis and is characterized in part by increased DNA synthesis (34); altered functional receptor expression, including receptors involved in growth factor signaling (29); and subcellular/ ultrastructure morphology (35,38,47). In cells from diseased vessels, Ca 2ϩ regulation is also altered (18) and implicated in increased vessel tone and vasospasm (27, 28). We recently reported that localized Ca 2ϩ signaling...

Amplitude modulation of nuclear Ca2+ signals in human skeletal myotubes: A possible role for nuclear Ca2+ buffering

“…Similar results were obtained with cardiomyocytes [40] and coronary smooth muscle cells [41]. Therefore in the model, sarcoplasmic Ca 2+ removal (accounted for by a single time constant λ) was considered to be inhomogeneous, being highest just outside the nucleus.…”

Beneficial effects of isometric strength training on endothelial dysfunction in rats

“…Our findings are in accordance with the existing literature. Indeed, Wamhoff et al (2002) reported, in adult female swine, that endurance exercise training enhances nuclear Ca 2+ regulation, possibly via SERCAs, localized very near the sarcolemma and along the rim of the nucleus to regulate Ca 2+ . Moreover, the fact that the ACh response was reduced by thapsigargin in the trained animals could suggest that the drug's effects on endothelium are greater than those on smooth muscle.…”

“…Therefore, the second aim of the study was to elucidate the possible mechanisms involved in vascular reactivity modifications after isometric exercise training. Current evidences suggest an involvement of several pathways such as endothelial NO (Sessa et al 1994;Kojda et al 2001;Hambrecht et al 2003), vasodilator prostaglandins (Koller et al 1995), ATP-dependent Ca 2+ pumps of the sarcoplasmic reticulum or endoplasmic reticulum (SERCA) (Wamhoff et al 2002), or calcium-sensitive potassium (K Ca ) channels (Chen et al 2001). Thus, an NO synthase blocker, a cyclooxygenase blocker, SERCA blockers, and K Ca channel inhibitors were used in the present study.…”

Excitation–Transcription Coupling in Arterial Smooth Muscle

“…Although limited, there is evidence that SMC nuclear Ca 2ϩ regulation can be altered in response to physiological or pathophysiological stimuli, eg, vascular disease, such that the amplitude and duration of nuclear Ca 2ϩ responses to contractile agonists are severely altered. 76,77 Whether this alters gene expression remains to be determined.…”