title: Mitochondriocentric pathway to cardiomyocyte necrosis in aldosteronism: cardioprotective responses to carvedilol and nebivolol.
abstract: 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 [Ca(2+)]i and SSM free [Ca(2+)]m; increased H(2)O(2) 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 [Zn(2+)]i were overwhelmed. Cotreatment with either Carv or Nebiv attenuated [Ca(2+)]i and [Ca(2+)]m overloading, prevented oxidative stress, and reduced mPTP opening while augmenting [Zn(2+)]i and conferring cardioprotection. Thus, major components of the mitochondriocentric signal-transducer-effector pathway to cardiomyocyte necrosis seen with ALDOST include intracellular Ca 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.
authors.affiliation: Division of Cardiovascular Diseases, Department of Medicine University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Yaser
authors.initials: Y
authors.lastname: Cheema
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Sherrod
authors.forename: Wenyuan
authors.initials: W
authors.lastname: Zhao
authors.forename: Tieqiang
authors.initials: T
authors.lastname: Zhao
authors.forename: Robert A
authors.initials: RA
authors.lastname: Ahokas
authors.forename: Yao
authors.initials: Y
authors.lastname: Sun
authors.forename: Ivan C
authors.initials: IC
authors.lastname: Gerling
authors.forename: Syamal K
authors.initials: SK
authors.lastname: Bhattacharya
authors.forename: Karl T
authors.initials: KT
authors.lastname: Weber
mesh_terms: D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology / Q000627:therapeutic use*; D002227:Carbazoles / Q000494:pharmacology / Q000627:therapeutic use*; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000077261:Carvedilol; D004983:Ethanolamines / Q000494:pharmacology / Q000627:therapeutic use*; D006929:Hyperaldosteronism / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D000068577:Nebivolol; D009336:Necrosis; D011412:Propanolamines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D001578:Benzopyrans; D002227:Carbazoles; D002316:Cardiotonic Agents; D004983:Ethanolamines; D033681:Mitochondrial Membrane Transport Proteins; D011412:Propanolamines; D000068577:Nebivolol; D000077261:Carvedilol