Chronic aldosterone/salt treatment (ALDOST) is accompanied by an adverse structural remodeling of myocardium that includes multiple foci of microscopic scarring representing morphologic footprints of cardiomyocyte necrosis. Our previous studies suggested that signal-transducer-effector pathway leading to necrotic cell death during ALDOST includes intramitochondrial Ca2+ overloading, together with an induction of oxidative stress and opening of the mitochondrial permeability transition pore (mPTP). To further validate this concept, we hypothesized that mitochondria-targeted interventions will prove to be cardioprotective. Accordingly, 8-week-old male Sprague-Dawley rats receiving 4 weeks ALDOST were cotreated with either quercetin, a flavonoid with mitochondrial antioxidant properties, or cyclosporine A (CsA), an mPTP inhibitor, and compared with ALDOST alone or untreated, age/sex-matched controls. We monitored mitochondrial free Ca2+ and biomarkers of oxidative stress, including 8-isoprostane and H2O2 production; mPTP opening; total Ca2+ in cardiac tissue; and collagen volume fraction to quantify replacement fibrosis, a biomarker of cardiomyocyte necrosis, and employed terminal deoxynucleotidyl transferase dUTP nick end labeling assay to address apoptosis in coronal sections of ventricular myocardium. Compared with controls, at 4 weeks ALDOST we found a marked increase in mitochondrial H2O2 production and 8-isoprostane levels, an increased propensity for mPTP opening, and greater concentrations of mitochondrial free [Ca2+]m and total tissue Ca2+, coupled with a 5-fold rise in collagen volume fraction without any terminal deoxynucleotidyl transferase dUTP nick end labeling-based evidence of cardiomyocyte apoptosis. Each of these pathophysiologic responses to ALDOST was prevented by quercetin or cyclosporine A cotreatment. Thus, mitochondria play a central role in initiating the cellular-subcellular mechanisms that lead to necrotic cell death and myocardial scarring. This destructive cycle can be interrupted and myocardium salvaged with its structure preserved by mitochondria-targeted cardioprotective strategies.
From the *Division of Cardiovascular Diseases, Department of Medicine, †Department of Surgery, ‡Department of Obstetrics & Gynecology, and §Division of Endocrinology, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN.
Received for publication July 12, 2010; accepted September 21, 2010.
Supported, in part, by National Institutes of Health grants R01-HL73043 and R01-HL90867 (K.T.W.).
The contents of the article are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.
Authors have no conflicts of interest to disclose.
Reprints: Karl T. Weber, MD, Division of Cardiovascular Diseases, University of Tennessee Health Science Center, 956 Court Avenue, Suite A312, Memphis, TN 38163 (e-mail: KTWeber@uthsc.edu).