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A Mitochondriocentric Pathway to Cardiomyocyte Necrosis: An Upstream Molecular Mechanism in Myocardial Fibrosis

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Cardiac Remodeling

Part of the book series: Advances in Biochemistry in Health and Disease ((ABHD,volume 5))

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.

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Abbreviations

ALDO:

Aldosterone

ALDOST:

Aldosterone/salt treatment

CHF:

Congestive heart failure

CVF:

Collagen volume fraction

DOCST:

Deoxycorticosterone/salt treatment

HHD:

Hypertensive heart disease

mPTP:

Mitochondrial permeability transition pore

MSTE:

Mitochondriocentric signal-transducer–effector

PAC:

Plasma aldosterone concentration

PTH:

Parathyroid hormone

RAAS:

Renin–angiotensin–aldosterone system

ROS:

Reactive oxygen species

SHPT:

Secondary hyperparathyroidism

Spiro:

Spironolactone

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Acknowledgments

This work was supported, in part, by NIH grants R01-HL73043 and R01-HL90867 (KTW). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

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Authors and Affiliations

  1. Division of Cardiovascular Diseases, University of Tennessee Health Science Center, 956 Court Avenue, Suite A312, Memphis, TN, USA

    Adedayo A. Adeboye, Kevin P. Newman, Dwight A. Dishmon, Shadwan Alsafwah, Syamal K. Bhattacharya & Karl T. Weber M.D.

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  1. Adedayo A. Adeboye
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  2. Kevin P. Newman
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  3. Dwight A. Dishmon
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  4. Shadwan Alsafwah
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  5. Syamal K. Bhattacharya
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  6. Karl T. Weber M.D.
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Corresponding author

Correspondence to Karl T. Weber M.D. .

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Editors and Affiliations

  1. Walter MacKenzie Health Sciences Centre, Division of Cardiology, University of Alberta, 8440-112 Street, Edmonton, T6G 2B7, Alberta, Canada

    Bodh I. Jugdutt

  2. St. Boniface General Hospital Research C, Institute of Cardiovascular Sciences, Tache Avenue 351, Winnipeg, R2H 2A6, Manitoba, Canada

    Naranjan S. Dhalla

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Adeboye, A.A., Newman, K.P., Dishmon, D.A., Alsafwah, S., Bhattacharya, S.K., Weber, K.T. (2013). A Mitochondriocentric Pathway to Cardiomyocyte Necrosis: An Upstream Molecular Mechanism in Myocardial Fibrosis. In: Jugdutt, B., Dhalla, N. (eds) Cardiac Remodeling. Advances in Biochemistry in Health and Disease, vol 5. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5930-9_7

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