A Mitochondriocentric Pathway to Cardiomyocyte Necrosis: An Upstream Molecular Mechanism in Myocardial Fibrosis
The pathophysiologic origins of heart failure can be attributed to a pathologic remodeling of myocardium, including necrotic loss of cardiomyocytes and consequent reparative fibrosis. Hypertensive heart disease with concentric left ventricular hypertrophy
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A Mitochondriocentric Pathway to Cardiomyocyte Necrosis: An Upstream Molecular Mechanism in Myocardial Fibrosis Adedayo A. Adeboye, Kevin P. Newman, Dwight A. Dishmon, Shadwan Alsafwah, Syamal K. Bhattacharya, and Karl T. Weber
Abstract The pathophysiologic origins of heart failure can be attributed to a pathologic remodeling of myocardium, including necrotic loss of cardiomyocytes and consequent reparative fibrosis. Hypertensive heart disease with concentric left ventricular hypertrophy and fibrosis represents a major etiologic factor accounting for diastolic heart failure. Herein, we focus on molecular mechanisms to the precursor of fibrosis, namely, cardiomyocyte necrosis, whose pathogenic origin resides in a mitochondriocentric signal-transducer–effector pathway. Its major components include intracellular Ca2+ overloading of cytosolic and mitochondrial domains, the induction of oxidative stress by these organelles which overwhelms endogenous antioxidant defenses, and the increased opening potential of the mitochondrial permeability transition pore. Novel cardioprotective strategies aimed at preventing the progressive remodeling of the failing heart should target upstream molecular mechanisms that prevent cardiomyocyte necrosis rather than downstream events involving collagen turnover related to fibrosis. Keywords Mitochondria • Calcium overload • Oxidative stress • Necrosis • Fibrosis • Aldosteronism
Abbreviations ALDO ALDOST CHF
Aldosterone Aldosterone/salt treatment Congestive heart failure
A.A. Adeboye • K.P. Newman • D.A. Dishmon • S. Alsafwah S.K. Bhattacharya • K.T. Weber, M.D. (*) Division of Cardiovascular Diseases, University of Tennessee Health Science Center, 956 Court Avenue, Suite A312, Memphis, TN, USA e-mail: [email protected] B.I. Jugdutt and N.S. Dhalla (eds.), Cardiac Remodeling: Molecular Mechanisms, Advances in Biochemistry in Health and Disease 5, DOI 10.1007/978-1-4614-5930-9_7, © Springer Science+Business Media New York 2013
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CVF DOCST HHD mPTP MSTE PAC PTH RAAS ROS SHPT Spiro
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Collagen volume fraction Deoxycorticosterone/salt treatment Hypertensive heart disease Mitochondrial permeability transition pore Mitochondriocentric signal-transducer–effector Plasma aldosterone concentration Parathyroid hormone Renin–angiotensin–aldosterone system Reactive oxygen species Secondary hyperparathyroidism Spironolactone
Introduction
The congestive heart failure (CHF) syndrome has reached epidemic proportions; its debilitating symptoms and signs account for the number one admitting diagnosis to US hospitals. CHF strains our workforce and drains our health-care economy. Of necessity, improved management strategies have become national priorities. A pathologic remodeling of myocardium contributes to the failure of this muscular pump during systolic and/or diastolic phases of the cardiac cycle and is related to (a) the loss of contractile parenchyma or cardiomyocytes and (b) their consequent replacement by extracellular matrix or reparative fibrosis. Foci of fibr
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