| Cation dyshomeostasis and cardiomyocyte necrosis: the Fleckenstein hypothesis revisited. | |
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MedLine Citation:
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PMID: 21398641 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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An ongoing loss of cardiomyocytes to apoptotic and necrotic cell death pathways contributes to the progressive nature of heart failure. The pathophysiological origins of necrotic cell loss relate to the neurohormonal activation that accompanies acute and chronic stressor states and which includes effector hormones of the adrenergic nervous system. Fifty years ago, Albrecht Fleckenstein and coworkers hypothesized the hyperadrenergic state, which accompanies such stressors, causes cardiomyocyte necrosis based on catecholamine-initiated excessive intracellular Ca(2+) accumulation (EICA), and mitochondrial Ca(2+) overloading in particular, in which the ensuing dysfunction and structural degeneration of these organelles leads to necrosis. In recent years, two downstream factors have been identified which, together with EICA, constitute a signal-transducer-effector pathway: (i) mitochondria-based induction of oxidative stress, in which the rate of reactive oxygen metabolite generation exceeds their rate of detoxification by endogenous antioxidant defences; and (ii) the opening of the mitochondrial inner membrane permeability transition pore (mPTP) followed by organellar swelling and degeneration. The pathogenesis of stress-related cardiomyopathy syndromes is likely related to this pathway. Other factors which can account for cytotoxicity in stressor states include: hypokalaemia; ionized hypocalcaemia and hypomagnesaemia with resultant elevations in parathyroid hormone serving as a potent mediator of EICA; and hypozincaemia with hyposelenaemia, which compromise antioxidant defences. Herein, we revisit the Fleckenstein hypothesis of EICA in leading to cardiomyocyte necrosis and the central role played by mitochondria. |
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Authors:
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Brian J Borkowski; Yaser Cheema; Atta U Shahbaz; Syamal K Bhattacharya; Karl T Weber |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-3-12 |
Journal Detail:
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Title: European heart journal Volume: - ISSN: 1522-9645 ISO Abbreviation: - Publication Date: 2011 Mar |
Date Detail:
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Created Date: 2011-3-14 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8006263 Medline TA: Eur Heart J Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Division of Cardiovascular Diseases, University of Tennessee Health Science Center, 956 Court Ave., Suite A312, Memphis, TN 38162, USA. |
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