Targets for Pharmacological Modulation of Cardiac Fibrosis

Brown, Lindsay; Chan, Vincent; Fenning, Andrew

doi:10.1007/0-387-22825-x_14

Cited by 2 publications

(2 citation statements)

References 181 publications

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“…In addition, OPN expression coincides with tissue degeneration in the myocardium and coronary arteries, and its cytokine-like mode of action promotes tissue remodeling via binding to integrins and modulation of extracellular matrix formation [3] , [4] . Similarly, an increased expression PAI-1 and TIMP-1 that contributes to extracellular matrix deposition has been observed in the hearts and kidneys of patients with chronic heart and kidney failure [2] , [7] – [10] , [1] , [31] . A direct molecular mechanism linking sGC stimulation and regulation of the expression of these genes has not been identified yet.…”

Section: Discussionmentioning

confidence: 99%

Soluble Guanylate Cyclase Stimulation Prevents Fibrotic Tissue Remodeling and Improves Survival in Salt-Sensitive Dahl Rats

et al. 2011

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BackgroundA direct pharmacological stimulation of soluble guanylate cyclase (sGC) is an emerging therapeutic approach to the management of various cardiovascular disorders associated with endothelial dysfunction. Novel sGC stimulators, including riociguat (BAY 63-2521), have a dual mode of action: They sensitize sGC to endogenously produced nitric oxide (NO) and also directly stimulate sGC independently of NO. Little is known about their effects on tissue remodeling and degeneration and survival in experimental malignant hypertension.Methods and ResultsMortality, hemodynamics and biomarkers of tissue remodeling and degeneration were assessed in Dahl salt-sensitive rats maintained on a high salt diet and treated with riociguat (3 or 10 mg/kg/d) for 14 weeks. Riociguat markedly attenuated systemic hypertension, improved systolic heart function and increased survival from 33% to 85%. Histological examination of the heart and kidneys revealed that riociguat significantly ameliorated fibrotic tissue remodeling and degeneration. Correspondingly, mRNA expression of the pro-fibrotic biomarkers osteopontin (OPN), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and plasminogen activator inhibitor-1 (PAI-1) in the myocardium and the renal cortex was attenuated by riociguat. In addition, riociguat reduced plasma and urinary levels of OPN, TIMP-1, and PAI-1.ConclusionsStimulation of sGC by riociguat markedly improves survival and attenuates systemic hypertension and systolic dysfunction, as well as fibrotic tissue remodeling in the myocardium and the renal cortex in a rodent model of pressure and volume overload. These findings suggest a therapeutic potential of sGC stimulators in diseases associated with impaired cardiovascular and renal functions.

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Section: Discussionmentioning

confidence: 99%

Soluble Guanylate Cyclase Stimulation Prevents Fibrotic Tissue Remodeling and Improves Survival in Salt-Sensitive Dahl Rats

et al. 2011

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“…The complexity of collagen synthesis and degradation provides several points of attack for pharmacological therapy to prevent deposition of collagens (7). The precise mechanisms underlying the observed reduction in collagen deposition in DOCA-salt hypertensive rats observed after L-arginine treatment are not known.…”

Section: Discussionmentioning

confidence: 99%

l-Arginine attenuates cardiovascular impairment in DOCA-salt hypertensive rats

Fenning¹,

Harrison²,

Rose’Meyer³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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Nitric oxide (NO) is essential for normal function of the cardiovascular system. This study has determined whether chronic administration of l-arginine, the biological precursor of NO, attenuates the development of structural and functional changes in hearts and blood vessels of deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Uninephrectomized rats treated with DOCA (25 mg every 4th day sc) and 1% NaCl in the drinking water for 4 wk were treated with l-arginine (5% in food, 3.4 ± 0.3 g·kg body wt−1·day−1). Changes in cardiovascular structure and function were determined by echocardiography, microelectrode studies, histology, and studies in isolated hearts and thoracic aortic rings. DOCA-salt hypertensive rats developed hypertension, left ventricular hypertrophy with increased left ventricular wall thickness and decreased ventricular internal diameter, increased inflammatory cell infiltration, increased ventricular interstitial and perivascular collagen deposition, increased passive diastolic stiffness, prolonged action potential duration, increased oxidative stress, and inability to increase purine efflux in response to an increased workload. l-Arginine markedly attenuated or prevented these changes and also normalized the reduced efficacy of norepinephrine and acetylcholine in isolated thoracic aortic rings of DOCA-salt hypertensive rats. This study suggests that a functional NO deficit in blood vessels and heart due to decreased NO synthase activity or increased release of reactive oxygen species such as superoxide may be a key change initiating many aspects of the cardiovascular impairment observed in DOCA-salt hypertensive rats. These changes can be prevented or attenuated by administration of l-arginine.

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Targets for Pharmacological Modulation of Cardiac Fibrosis

Cited by 2 publications

References 181 publications

Soluble Guanylate Cyclase Stimulation Prevents Fibrotic Tissue Remodeling and Improves Survival in Salt-Sensitive Dahl Rats

Soluble Guanylate Cyclase Stimulation Prevents Fibrotic Tissue Remodeling and Improves Survival in Salt-Sensitive Dahl Rats

l-Arginine attenuates cardiovascular impairment in DOCA-salt hypertensive rats

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