Exercise, estrogen, and ischemic cardioprotection by heat shock protein 70.

Acute ischemic injury and myocardial infarction arising from coronary artery disease, despite significant strides in medical and surgical management, remain a major public problem. Sex disparity has long been recognized for coronary ischemic events: premenopausal women are at reduced risk for atherosclerotic disease than men of similar age, an advantage that vanishes after menopause.1 The beneficial effects of estrogen are known to modify vasomotor tone, vascular integrity, blood pressure, lipid profiles, and cholesterol metabolism. However, far less is known about the sex-related effects estrogen has on stress-activated pathways such as the chaperone defense mechanism, which plays fundamental roles in reducing oxidative damage ensuing from myocardial ischemia and reperfusion injury.2,3 In this issue of Circulation Research, Paroo and coworkers4 have addressed the hypothesis that sexual dimorphism in cardiac heat shock protein 70 (Hsp70) expression induced by exercise is modulated by estrogen and that such effects confer sex-specific protection against ischemic injury. These investigators have shown that a single exercise regimen, 30 m/min for 60 minutes, leads to the induction of Hsp70 expression by 2-fold (24 hours) in male but not in female rats. Whereas exercise upregulates Hsp70 expression in ovariectomized female rats, estrogen replacement abrogates similar effects, suggesting that estrogen plays a key role to repress exerciseinduced stress response (in a sex-specific manner). Furthermore, a direct causal mechanism by Hsp70 in mediating the recovery of postischemic cardiac function was convincingly shown using antisense oligonucleotides, an approach that had been previously reported to abrogate Hsp70-dependent protection against simulated ischemia in adult cardiac myocytes5 but not yet in the intact postischemic heart (the present study by Paroo et al4). What are the mechanisms by which sex-linked Hsp70 expression mediate ischemic protection? Paroo et al4 have focused their study on Hsp70, which belongs to the multigene family of heat shock genes (hsp), encoding intracellular proteins triggered by heat shock and various other stressful conditions. Molecular chaperones such as HSP might be cytoprotective agents, which effectively retard protein conformational abnormalities implicated, in part, in the pathogenesis of age-related oxidative damage, atherosclerosis, and myocardial ischemia and reperfusion injury. The findings reported here are consistent with previous studies that have reported forced overexpression of Hsp70 affords effective protection against myocardial injury, reduces postischemic ventricular dysfunction, and improves ATP synthesis (see reviews2,6). At the molecular level, antiapoptotic effects of Hsp70 might mediate cardioprotection by directly counteracting the functions of proapoptotic Apaf1, caspase recruitment domain (CARD), and apoptosome formation.7 Several additional aspects of this study deserve comment. First, it is surprising to some that the exercise regimen does not stimulate Hsp25/7 expression, which others have reported in different postexercise skeletal muscles.8 As shown for several HSPs, a high constitutive level of Hsp25/7 expression correlates inversely with its stress-inducible upregulation and synthesis (see data in Xiao et al9). Another notable limitation is the assumption that cardiac myocytes per se are the principal targets of protection against ischemia/reperfusion injury. Last, in addition to Hsp70, the salutary effects exerted by exercise-induced cross-tolerance after 24 hours might also include adaptive changes driven by nitric oxide.10 The physiological roles of stress “heat shock” proteins are inextricably linked to their transcriptional regulation, which is mediated by a family of transcriptional regulators, collectively known as heat shock transcription factors (HSFs). Various stressful conditions that promote protein instability and denaturation release HSF1 from interacting partners, enabling it to oligomerize as transcriptionally competent homotrimers. Activated HSF1 exhibits increased phosphorylation and a high-affinity binding to heat shock elements arranged as arrays of inverted pentanucleotide repeats (nGAAn) in the promoters of target hsp genes. Indeed, increased oxidative stress can play an important role, as reactive oxygen species (ROS)-mediated HSF1 activation has been reported during upregulation of heat shock proteins by myocardial ischemia/reperfusion.11 In addition to pathological stimuli,2 physiological conditions such as exercise can also stimulate Hsp70 expression in the myocardium,12 skeletal muscle,13 even in human leukocytes,14 probably through HSF1 activity. How might estrogen per se attenuate Hsp70 expression induced by exercise? The present study does not provide direct answers, but the investigators have commendably addressed a few important possibilities. The effects of estrogen could be mediated by its receptors, estrogen receptor and estrogen receptor , homologous members of the superfamily of steroid hormone receptors, which are expressed in The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Department of Internal Medicine, Molecular Cardiology Research Laboratories, the University of Texas Southwestern Medical Center, Dallas, Tex. Correspondence to Ivor J. Benjamin, Department of Internal Medicine & Division of Cell and Molecular Biology, UT Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX 75390-8573. E-mail [email protected] (Circ Res. 2002;90:833-835.) © 2002 American Heart Association, Inc.