title: Cellular and molecular pathways to myocardial necrosis and replacement fibrosis.
abstract: Fibrosis is a fundamental component of the adverse structural remodeling of myocardium present in the failing heart. Replacement fibrosis appears at sites of previous cardiomyocyte necrosis to preserve the structural integrity of the myocardium, but not without adverse functional consequences. The extensive nature of this microscopic scarring suggests cardiomyocyte necrosis is widespread and the loss of these contractile elements, combined with fibrous tissue deposition in the form of a stiff in-series and in-parallel elastic elements, contributes to the progressive failure of this normally efficient muscular pump. Cellular and molecular studies into the signal-transducer-effector pathway involved in cardiomyocyte necrosis have identified the crucial pathogenic role of intracellular Ca2+ overloading and subsequent induction of oxidative stress, predominantly confined within its mitochondria, to be followed by the opening of the mitochondrial permeability transition pore that leads to the destruction of these organelles and cells. It is now further recognized that Ca2+ overloading of cardiac myocytes and mitochondria serves as a prooxidant and which is counterbalanced by an intrinsically coupled Zn2+ entry serving as antioxidant. The prospect of raising antioxidant defenses by increasing intracellular Zn2+ with adjuvant nutriceuticals can, therefore, be preferentially exploited to uncouple this intrinsically coupled Ca2+ - Zn2+ dyshomeostasis. Hence, novel yet simple cardioprotective strategies may be at hand that deserve to be further explored.
authors.affiliation: Division of Cardiovascular Diseases, Department of Medicine, University of Tennessee Health Science Center, 956 Court Ave., Suite A312, Memphis, TN 38163, USA.
authors.forename: Malay S
authors.initials: MS
authors.lastname: Gandhi
authors.forename: German
authors.initials: G
authors.lastname: Kamalov
authors.forename: Atta U
authors.initials: AU
authors.lastname: Shahbaz
authors.forename: Syamal K
authors.initials: SK
authors.lastname: Bhattacharya
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: Karl T
authors.initials: KT
authors.lastname: Weber
mesh_terms: D000450:Aldosterone; D000818:Animals; D004195:Disease Models, Animal; D005355:Fibrosis / Q000473:pathology*; D006333:Heart Failure / Q000473:pathology*; D006801:Humans; D053565:Hypercalciuria; D006962:Hyperparathyroidism, Secondary; D006996:Hypocalcemia; D052139:Intracellular Calcium-Sensing Proteins; D008928:Mitochondria; D009206:Myocardium / Q000166:cytology / Q000473:pathology*; D009336:Necrosis / Q000473:pathology*; D009397:Nephrocalcinosis; D018384:Oxidative Stress; D015499:Renal Tubular Transport, Inborn Errors; D020257:Ventricular Remodeling
chemical_list: D052139:Intracellular Calcium-Sensing Proteins; D000450:Aldosterone
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