"Roid-Rage" at the cellular level: abolition of endogenous cardioprotection by anabolic steroids reveals new links between the RAAS and cardiac KATP channels : editorial to: "AT1 and aldosterone receptors blockade prevents the chronic effect of nandrolone on the exercise-induced cardioprotection in perfused rat heart subjected to ischemia and reperfusion" by S.R. Marques-Neto et al.

Substantial evidence suggests that androgenic anabolic steroids (AAS) have deleterious effects on many body tissues, but their influence on endogenous mechanisms of cardioprotection is poorly understood. In the current issue of CDT, Marques-Neto et al. present a study examining the mechanisms by which AAS attenuate the protective effects of exercise training on myocardial ischemia/ reperfusion injury [1]. They chose to focus on the roles of angiotensin II and aldosterone, given the wellestablished stimulatory effect of AAS on the renin angiotensin-aldosterone system (RAAS) and the role of this system in the pathogenesis of myocardial injury. Exercise-trained rats were co-administered nandralone (AAS) along with losartan or spironolactone to block AT1 or aldosterone receptors, followed by evaluation of post-ischemic function and infarct size in isolated perfused hearts. Their results show that nandralone abolishes the benefits of exercise training on post-ischemic function and infarct size reduction, and that both RAAS blockers restore these benefits, confirming the hypothesized role of the RAAS in the AAS-induced suppression of exercise-induced cardioprotection. In this study, Marques-Neto et al. link the preservation of cardioprotection to maintenance of myocardial sarcolemmal ATP-sensitive potassium (sarcKATP) channel expression. sarcKATP channels are highly expressed in the cardiac sarcolemma, and open in response to local changes in nucleotide content (reviewed in [2–4]). A growing body of literature supports a positive correlation between sarcKATP expression and cardioprotection [5, 6]. Preconditioning conferred by exercise is associated with enhanced sarcKATP channel subunits [7], and genetic loss of sarcKATP channels confers exercise intolerance and poor adaptation of the heart to stress [8]. sarcKATP channel expression is also believed to mediate sex-dependent protection against cardiac injury. While women are known to exhibit reduced risk of cardiovascular events and associated mortality compared to males, the molecular mechanisms of this sex-dimorphism remains incompletely understood [9–11]. Animal studies have demonstrated an intrinsic resistance of the female heart to ischemia/ reperfusion injury, which has been linked to a higher expression of sarcKATP channel subunits in the female versus male heart [6, 12–14]. Estrogen upregulates sarcKATP channel subunit expression in cardiomyocytes [15], suggesting a potential mechanism for its protective effects in the heart. Clinical studies indicate that pharmacological interventions that block sarcKATP channels to manage disease symptoms are associated with increased cardiovascular mortality [16, 17], further suggesting an important protective role of these channels on cardiovascular health. Despite the relationship between cardiac tissue health and sarcKATP expression, the cellular mechanisms responsible for altering the expression of these channels are not clear. The study by Marques-Neto et al. implicates the RAAS in androgenic suppression of sarcKATP and exercise-induced A. J. Chicco (*) Departments of Health and Exercise Science and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA e-mail: adam.chicco@colostate.edu