Mitochondriocentric Pathway to Cardiomyocyte Necrosis in Aldosteronism: Cardioprotective Responses to Carvedilol and Nebivolol

Foci of fibrosis, footprints of cardiomyocyte necrosis, are scattered throughout the failing myocardium and are a major component to its pathologic remodeling. Understanding pathogenic mechanisms contributing to hormone-mediated necrosis is therefore fundamental to developing cardioprotective strategies. In this context, a mitochondriocentric signal-transducer-effector pathway to necrosis is emerging. Our first objective, using cardiomyocytes and subsarcolemmal mitochondria (SSM) harvested from rats receiving a 4-week aldosterone/salt treatment (ALDOST), was to identify the major components of this pathway. Second, to validate this pathway, we used mitochondria-targeted pharmaceutical interventions as cardioprotective strategies using 4-week cotreatment with either carvedilol (Carv) or nebivolol (Nebiv). Compared with controls, we found the 4-week ALDOST to be accompanied by elevated cardiomyocyte free [Ca2+](i) and SSM free [Ca2+](m); increased H2O2 production and 8-isoprostane in SSM, cardiac tissue, and plasma; and enhanced opening of mitochondrial permeability transition pore (mPTP) and myocardial scarring. Increments in the antioxidant capacity augmented by increased cytosolic free [Zn2+](i) were overwhelmed. Cotreatment with either Carv or Nebiv attenuated [Ca2+](i) and [Ca2+](m) overloading, prevented oxidative stress, and reduced mPTP opening while augmenting [Zn2+](i) and conferring cardioprotection. Thus, major components of the mitochondriocentric signal-transducer-effector pathway to cardiomyocyte necrosis seen with ALDOST include intracellular Ca2+ overloading coupled to oxidative stress and mPTP opening. This subcellular pathway can be favorably regulated by Carv or Nebiv cotreatment to salvage cardiomyocytes and prevent fibrosis.