Hypertensive heart disease (HHD) has its pathophysiologic origins arising from the reparative fibrosis, or scarring, that replaces necrotic cardiomyocytes. Understanding the pathobiology behind cardiomyocyte necrosis will lead to the prevention of HHD while the availability of biomarkers predictive of necrosis and obtained noninvasively from peripheral blood mononuclear cells (PBMC) will aid in identification of risk. In addressing these objectives we use our established model of HHD provoked by aldosterone/salt treatment (ALDOST) and exploit its preclinical (wk 1) and pathologic (wk 4) stages. Central hypothesis: in HHD, fibrosis at wk 4 is due to oxidative stress- induced cardiomyocyte necrosis, where the cell's altered redox state is rooted in parathyroid hormone (PTH)- mediated intracellular Ca2+ overloading, including cardiac myocytes and mitochondria and PBMC, and where the rate of reactive oxygen species (ROS) generation overwhelms the rate of their detoxification by endogenous antioxidant defenses. This 2C+-adependent induction of oxidative stress promotes the opening of the mitochondrial permeability transition pore (mPTP) to culminate i n necrosis. This prooxidant state can be counterbalanced by the contemporaneous rise in cytosolic and mitochondrial 2Z+nserving as antioxidant. We hypothesize the dysequilibrium between pro- and antioxidant is inextricably linked to the coupled dyshomeostasis of Ca2+ and Zn2+. Mitochondria are the major source of ROS.
Aim #1 : to determine the cellular and molecular origins of oxidative stress arising from intracellular C2+a overloading and the role of intra mitochondrial Ca2+ accumulation, oxidative stress and mPTP opening in the signal-transduction pathway leading to necrosis and to compare heart tissue and its cardiac myocytes and mitochondria with PBMCW.e use mitochondria-targeted reagents: to b lock the 2+Cau niporter;t o serve as antioxidant;and to inhibit mPTP. Necrosis is prevented by increased [Zn2+]i, which induces its sensor, metal-responsive transcription factor (MTF)-1 and the antioxidant genes it regulates. Such """"""""uncoupling therapy"""""""" includes: Zn4SOsupplement;PDTC, a Zn2+ ionophore;or ZnSO4 plus a mlodipine.
Aim # 2: to explore the signal-transduction antioxidant pathway invoked by increased intracellular [Zn2+]i and promoted by ZnSO4, PDTC, or ZnSO4 with amlodipine, along with the role of MTF-1 regulated antioxidant defenses that eventuate in an antioxidant, anti-inflammatory phenotype in cardiac myocytes and to compare heart tissue and its cardiomyocytes and mitochondria with PBMC. PBMC share common pathophysiologic responses and upregulated gene networks with cardiac myocytes and mitochondria during ALDOST. We harvest PBMC throughout Aims #1 and 2 in search of novel surrogate biomarkers of risk, injury and response to intervention.
Aim #3 : i) to identify major components of the PBMC transcriptome and proteome having molecular mimicry with the pro inflammatory cardiac phenotype, including its mitochondrial proteome, and ii) to elucidate specific pathway candidates that could serve as noninvasive biomarkers predictive of risk during preclinical and pathologic stages of HHD.

Public Health Relevance

Heart failure is a major health problem. Hypertensive heart disease (HHD), a major factor contributing to the heart's failure as a muscular pump, involves an adverse structural remodeling of myocardium related to fibrosis. Our aim is to better understand mechanisms contributing to the appearance of fibrosis and to thereby identify risk and prevention of HHD.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Special Emphasis Panel (ZRG1-CVRS-F (02))
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Adhikari, Bishow B
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University of Tennessee Health Science Center
Internal Medicine/Medicine
Schools of Medicine
United States
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Al Darazi, Fahed; Zhao, Wenyuan; Zhao, Tieqiang et al. (2014) Small dedifferentiated cardiomyocytes bordering on microdomains of fibrosis: evidence for reverse remodeling with assisted recovery. J Cardiovasc Pharmacol 64:237-46
Efeovbokhan, Nephertiti; Bhattacharya, Syamal K; Ahokas, Robert A et al. (2014) Zinc and the prooxidant heart failure phenotype. J Cardiovasc Pharmacol 64:393-400
Seawell, Michael R; Al Darazi, Fahed; Farah, Victor et al. (2013) Mineralocorticoid receptor antagonism confers cardioprotection in heart failure. Curr Heart Fail Rep 10:36-45
Khan, M Usman; Cheema, Yaser; Shahbaz, Atta U et al. (2012) Mitochondria play a central role in nonischemic cardiomyocyte necrosis: common to acute and chronic stressor states. Pflugers Arch 464:123-31
Yusuf, Jawwad; Khan, M Usman; Cheema, Yaser et al. (2012) Disturbances in calcium metabolism and cardiomyocyte necrosis: the role of calcitropic hormones. Prog Cardiovasc Dis 55:77-86
Shahbaz, Atta U; Kamalov, German; Zhao, Wenyuan et al. (2011) Mitochondria-targeted cardioprotection in aldosteronism. J Cardiovasc Pharmacol 57:37-43
Cheema, Yaser; Sherrod, Jonathan N; Zhao, Wenyuan et al. (2011) Mitochondriocentric pathway to cardiomyocyte necrosis in aldosteronism: cardioprotective responses to carvedilol and nebivolol. J Cardiovasc Pharmacol 58:80-6
Gandhi, Malay S; Kamalov, German; Shahbaz, Atta U et al. (2011) Cellular and molecular pathways to myocardial necrosis and replacement fibrosis. Heart Fail Rev 16:23-34
Kamalov, German; Bhattacharya, Syamal K; Weber, Karl T (2010) Congestive heart failure: where homeostasis begets dyshomeostasis. J Cardiovasc Pharmacol 56:320-8
Shahbaz, Atta U; Sun, Yao; Bhattacharya, Syamal K et al. (2010) Fibrosis in hypertensive heart disease: molecular pathways and cardioprotective strategies. J Hypertens 28 Suppl 1:S25-32

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