Effects of endothelins on collagen turnover in cardiac fibroblasts

Guarda, Eduardo; Katwa, Laxmansa C.; Myers, Paul R.; Tyagi, Suresh C.; Weber, Karl T.

doi:10.1093/cvr/27.12.2130

Cited by 281 publications

(137 citation statements)

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“…26 The early release of TGF-␤1 from necrotic myocytes and macrophages is also important in the phenotypic transformation of interstitial fibroblasts to myofibroblasts, which elaborate receptors to Ang II, TGF-␤1, and ET-1. 26,28 Myofibroblasts express genes encoding for procollagen types 1 and 3, generate Ang I and II and receptors for Ang II and TGF-␤1 and ET-1; this enables the autoregulation of collagen turnover. 4,26 Synthesis of collagen types 1 and 3 by myofibroblasts is modulated by several factors, including Ang II-related mechanical deformation, fibroblast growth factor, platelet-derived growth factor, ANP, and bradykininmediated prostaglandin E2 and nitric oxide release.…”

Section: Triggers For Tissue Repairmentioning

confidence: 99%

Left Ventricular Remodeling After Myocardial Infarction

2000

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L eft ventricular remodeling is the process by which ventricular size, shape, and function are regulated by mechanical, neurohormonal, and genetic factors. 1,2 Remodeling may be physiological and adaptive during normal growth or pathological due to myocardial infarction, cardiomyopathy, hypertension, or valvular heart disease ( Figure 1). This article will review postinfarction remodeling, pathophysiological mechanisms, and therapeutic intervention. Pathophysiology Postinfarction Left Ventricular RemodelingThe acute loss of myocardium results in an abrupt increase in loading conditions that induces a unique pattern of remodeling involving the infarcted border zone and remote noninfarcted myocardium. Myocyte necrosis and the resultant increase in load trigger a cascade of biochemical intracellular signaling processes that initiates and subsequently modulates reparative changes, which include dilatation, hypertrophy, and the formation of a discrete collagen scar. Ventricular remodeling may continue for weeks or months until the distending forces are counterbalanced by the tensile strength of the collagen scar. This balance is determined by the size, location, and transmurality of the infarct, the extent of myocardial stunning, the patency of the infarct-related artery, and local tropic factors. 1,3 The myocardium consists of 3 integrated components: myocytes, extracellular matrix, and the capillary microcirculation that services the contractile unit assembly. Consideration of all 3 components provides important insights into the remodeling process and a rationale for future therapeutic strategies. The cardiomyocyte is terminally differentiated and develops tension by shortening. The extracellular matrix provides a stress-tolerant, viscoelastic scaffold consisting of type I and type III collagen that couples myocytes and maintains the spatial relations between the myofilaments and their capillary microcirculation. 4,5 The collagen framework couples adjacent myocytes by intercellular struts that align myofilaments to optimize force development, distribute force evenly to the ventricular walls, and prevent sarcomeric deformation. 5 Myocardial infarction results in the migration of macrophages, monocytes, and neutrophils into the infarct zone; this initiates intracellular signaling and neurohormonal activation, which localizes the inflammatory response. Changes in circulatory hemodynamics are determined primarily by the magnitude of myocyte loss, the stimulation of the sympathetic nervous system and renin-angiotensin-aldosterone system, and the release of natriuretic peptides.Postinfarction remodeling has been arbitrarily divided into an early phase (within 72 hours) and a late phase (beyond 72 hours). The early phase involves expansion of the infarct zone, 5 which may result in early ventricular rupture or aneurysm formation. Late remodeling involves the left ventricle globally and is associated with time-dependent dilatation, the distortion of ventricular shape, and mural hypertrophy. The failure to normalize increa...

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Section: Triggers For Tissue Repairmentioning

confidence: 99%

Left Ventricular Remodeling After Myocardial Infarction

2000

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“…3 H]Proline incorporation by cardiac fibroblasts was measured according to modified methods of Guarda et al (26). Briefly, cells were transferred to 12-well plates then were serum starved in 0% FBS for 24 h. Proline incorporation was then assayed by adding 1 Ci/well of [ 3 H]proline (PerkinElmer Life Sciences) along with, where indicated, drugs of interest and 2.5% FBS for 24 h. Cells were removed by trypsinization and protein precipitated overnight with 20% trichloroacetic acid.…”

Section: Assay Of Collagenase-sensitive [ 3 H]proline Incorporation-[mentioning

confidence: 99%

Angiotensin II Enhances Adenylyl Cyclase Signaling via Ca2+/Calmodulin

Ostrom¹,

Naugle

Hase³

et al. 2003

Journal of Biological Chemistry

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Cardiac fibroblasts regulate formation of extracellular matrix in the heart, playing key roles in cardiac remodeling and hypertrophy. In this study, we sought to characterize cross-talk between G q and G s signaling pathways and its impact on modulating collagen synthesis by cardiac fibroblasts. Angiotensin II (ANG II) activates cell proliferation and collagen synthesis but also potentiates cyclic AMP (cAMP) production stimulated by ␤-adrenergic receptors (␤-AR). The potentiation of ␤-AR-stimulated cAMP production by ANG II is reduced by phospholipase C inhibition and enhanced by overexpression of G q . Ionomycin and thapsigargin increased intracellular Ca 2؉ levels and potentiated isoproterenoland forskolin-stimulated cAMP production, whereas chelation of Ca 2؉ with 1,2-bis(2-aminophenoxy)ethane-N,N,N,N-tetraacetic acid/AM inhibited such potentiation. Inhibitors of tyrosine kinases, protein kinase C, or G␤␥ did not alter this cross-talk. Immunoblot analyses showed prominent expression of adenylyl cyclase 3 (AC3), a Ca 2؉ -activated isoform, along with AC2, AC4, AC5, AC6, and AC7. Of those isoforms, only AC3 and AC5/6 proteins were detected in caveolin-rich fractions. Overexpression of AC6 increased ␤AR-stimulated cAMP accumulation but did not alter the size of the ANG II potentiation, suggesting that the cross-talk is AC isoform-specific. Isoproterenol-mediated inhibition of serum-stimulated collagen synthesis increased from 31 to 48% in the presence of ANG II, indicating that ␤AR-regulated collagen synthesis increased in the presence of ANG II. These data indicate that ANG II potentiates cAMP formation via Ca 2؉ -dependent activation of AC activity, which in turn attenuates collagen synthesis and demonstrates one functional consequence of crosstalk between G q and G s signaling pathways in cardiac fibroblasts.

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“…Guarda et al 79 have found that endothelin-1 (ET-1) and ET-3 each increase cardiac fibroblast collagen synthesis and the synthesis of its types I and III phenotype in a concentration-dependent manner. Both ET A and ET B receptors were involved in this response.…”

Section: Endothelinsmentioning

confidence: 99%

Structural remodeling in hypertensive heart disease and the role of hormones.

1994

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In hypertension, the risk of adverse cardiovascular events, including heart failure, is increased in the presence of left ventricular hypertrophy. Morphological studies suggest that it is not the quantity but rather the quality, or structure, of myocardium that confers such risk. Iterations in tissue structure that appear in hypertensive heart disease include a remodeling of intramyocardial coronary arterioles, similar to that found in systemic organs, and a disproportionate accumulation of fibrillar collagen within their adventitia and neighboring interstitial space. Microscopic scars replacing necrotic cardiac myocytes are also evident. These expressions of fibrosis appear in the normotensive, nonhypertrophied right and hypertensive, hypertrophied left ventricles and are linked to the renin-angiotensin-aldosterone system. Cardiac myocyte growth, the major determinant of myocardial mass, is related to ventricular loading. Mechanisms responsible for the reactive and reparative fibrosis with renin-angiotensin-aldosterone system activation are under investigation. In vitro quantitative autoradiography has identified angiotensin II, aldosterone, T he appearance of symptomatic heart failure and adverse cardiovascular events, such as myocardial infarction, sudden cardiac death, and stroke, occur with increased frequency in patients with systemic hypertension. For years, the pathophysiologica] basis for such increased risk has been presumed to be solely related to elevated arterial pressure. More recently, emphasis in conferring risk has been placed on the structural remodeling of the cardiovasculature. For example, in patients with uncomplicated hypertension, risk has been linked to left ventricular hypertrophy (LVH). 13 Viewed not as a separate organ but as an integral component of the cardiovasculature, the heart and its intramyocardial coronary arteries and arterioles participate in a structural remodeling that involves systemic organs as well. 48 The remodeling of systemic arterioles accounts for hypertension. The heart in turn responds to enhanced ventricular loading with a hypertrophic growth of cardiac myocytes, and accordingly, left ventricular mass is increased. The diffuse nature of the structural remodeling process, involving the right and left ventricles and systemic organs, suggests a role for circulating substances or substances produced locally within cardiovascular tissue. In this connection, it is noteworthy that risk has also been linked to an activation of the renin-angiotensin-aldosterone system (RAAS). endothelin, and bradykinin receptors in the myocardium. A nonendothelial tissue angiotensin-converting enzyme, whose binding density is marked in the matrix of heart valves, adventitia, and sites of fibrosis, irrespective of its pathogenic basis, has also been found. This angiotensin-converting enzyme may be responsible for regulating local concentrations of angiotensin II and bradykinin that govern fibroblast collagen turnover. Based on a paradigm of discordant reciprocal regulation, in wh...

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Effects of endothelins on collagen turnover in cardiac fibroblasts

Cited by 281 publications

References 0 publications

Left Ventricular Remodeling After Myocardial Infarction

Left Ventricular Remodeling After Myocardial Infarction

Angiotensin II Enhances Adenylyl Cyclase Signaling via Ca2+/Calmodulin

Structural remodeling in hypertensive heart disease and the role of hormones.

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