Fibrosis in hypertensive heart disease: molecular pathways and cardioprotective strategies.
Fibrosis is a fundamental component of the adverse structural remodelling of myocardium found in hypertensive heart disease (HHD). A replacement fibrosis appears at sites of previous cardiomyocyte necrosis to preserve the structural integrity of the myocardium. Such scarring has adverse functional consequences. The extensive distribution of fibrosis involving the right and left heart suggests cardiomyocyte necrosis is widespread. Together, the loss of these contractile elements and fibrous tissue deposition in the form of stiff in-series and in-parallel elastic elements contribute to the progressive failure of this normally efficient muscular pump. Pathogenic mechanisms modulating fibrous tissue formation at sites of repair include auto/paracrine properties of locally generated angiotensin II and endothelin-1. This study focuses on the signal-transducer-effector pathway involved in cardiomyocyte necrosis and the crucial pathogenic role of intracellular calcium overloading, and the subsequent induction of oxidative stress originating within its mitochondria that dictates the opening of the mitochondrial permeability transition pore. The ensuing osmotic destruction of these organelles is followed by necrotic cell death. It is now further recognized that calcium overloading of cardiac myocytes and mitochondria functioning as pro-oxidant is pathophysiologically counterbalanced by an intrinsically coupled zinc entry, which serves as an antioxidant. The prospect of raising intracellular zinc by adjuvant nutriceutical supplementation can, therefore, be preferentially exploited to uncouple this intrinsically coupled calcium-zinc dyshomeostasis in favour of endogenous antioxidant defences. Novel cardioprotective strategies may thus be at hand and deserve to be explored further in the overall management of patients with HHD.
Shahbaz
Atta U
AU
University of Tennessee Health Science Center, 956 Court Ave., Memphis, TN 38163, USA.
Sun
Yao
Y
Bhattacharya
Syamal K
SK
Ahokas
Robert A
RA
Gerling
Ivan C
IC
McGee
Jesse E
JE
Weber
Karl T
KT
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D044383:Black People; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D005355:Fibrosis; D006331:Heart Diseases / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D006973:Hypertension / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000097:blood
D000975:Antioxidants; D002316:Cardiotonic Agents; D012083:Renin
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