科研之友
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摘要
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(2+) 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.
- 出版日期2011-7
