Role of transforming growth factor-beta in maintenance of function of cultured neonatal cardiac myocytes. Autocrine action and reversal of damaging effects of interleukin-1.

Roberts, Anita B.; Roche, Nanette S.; Winokur, Thomas S.; Burmester, James K.; Sporn, Michael B.

doi:10.1172/jci116087

Cited by 93 publications

(38 citation statements)

References 42 publications

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“…It is unlikely that TGF-␤ has the major impact on compensatory hypertrophy of the adult myocyte in response to pressure overload in this model, although TGF-␤ was reported to induce growth of cultured neonatal cardiac myocytes. 21 The effects of NAb on LV hypertrophy may be attributable to the reduction in myocardial fibrosis, because NAb did not affect myocyte hypertrophy and because the decrease in echocardiographic LV mass (15% reduction; Figure 7B) seems similar to that in % myocardial fibrosis (18% reduction; Figure 5A). …”

Section: Discussionmentioning

confidence: 90%

Transforming Growth Factor-β Function Blocking Prevents Myocardial Fibrosis and Diastolic Dysfunction in Pressure-Overloaded Rats

et al. 2002

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Background-Excessive myocardial fibrosis impairs cardiac function in hypertensive hearts. Roles of transforming growth factor (TGF)-␤ in myocardial remodeling and cardiac dysfunction were examined in pressure-overloaded rats. Methods and Results-Pressure overload was induced by a suprarenal aortic constriction in Wistar rats. Fibroblast activation (proliferation and phenotype transition to myofibroblasts) was observed after day 3 and peaked at days 3 to 7. Thereafter, myocyte hypertrophy and myocardial fibrosis developed by day 28. At day 28, echocardiography showed normal left ventricular fractional shortening, but the decreased ratio of early to late filling velocity of the transmitral Doppler velocity and hemodynamic measurement revealed left ventricular end-diastolic pressure elevation, indicating normal systolic but abnormal diastolic function. Myocardial TGF-␤ mRNA expression was induced after day 3, peaked at day 7, and remained modestly increased at day 28. An anti-TGF-␤ neutralizing antibody, which was administered intraperitoneally daily from 1 day before operation, inhibited fibroblast activation and subsequently prevented collagen mRNA induction and myocardial fibrosis, but not myocyte hypertrophy. Neutralizing antibody reversed diastolic dysfunction without affecting blood pressure and systolic function. Conclusions-TGF-␤ plays a causal role in myocardial fibrosis and diastolic dysfunction through fibroblast activation in pressure-overloaded hearts. Our findings may provide an insight into a new therapeutic strategy to prevent myocardial fibrosis and diastolic dysfunction in pressure-overloaded hearts.

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Section: Discussionmentioning

confidence: 90%

Transforming Growth Factor-β Function Blocking Prevents Myocardial Fibrosis and Diastolic Dysfunction in Pressure-Overloaded Rats

et al. 2002

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“…The developmental expression in the vessel wall has not been reported; however, this factor is highly expressed in neonatal tissues, such as the heart. 90 In the context of our observation on vascular angiotensin, it is interesting to note that ACE expression, which occurs at high levels in neonatal vessels, is increased in the aorta of rats with two-kidney, one clip hypertension. 91 Interestingly, treatment of young prehypertensive spontaneously hypertensive rats (SHR) with converting enzyme inhibitors will protect the animals from posttreatment increases in blood pressure.…”

Section: >79mentioning

confidence: 80%

New perspectives in hypertension research. Potentials of vascular biology.

et al. 1994

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The vessel wall was once considered to be a passive conduit responding to the circulating endocrine system. However, the emergence of molecular and vascular biology in hypertension research has redefined our understanding of the role of the vasculature as a vital organ in the pathogenesis of hypertension. It is now recognized that the vasculature can regulate its own tone by a variety of previously unknown autocrine and/or paracrine vasoactive systems. Recent evidence indicates that the process of vascular remodeling in hypertension appears to be mediated by locally generated factors within the vessel wall. This review examines the implications of this new paradigm in hypertension, focusing on O ver the past half century, the direction of hypertension research has been shaped by a scientific paradigm that has focused on the regulation of systemic neuroendocrine vasoactive systems that control vascular tone and renal fluid-electrolyte homeostasis. This paradigm postulates that hypertension is caused by a disturbance in the physiological homeostatic mechanisms regulating the levels of and/or responses to circulating hormones and sympathetic nervous system activity. In this schema the vasculature is conceptualized as a simple effector system that passively responds to the actions of systemic neuroendocrine factors. However, advances in molecular vascular biology have begun to promote a paradigm shift that has dramatically altered our conception of the role of the vasculature in hypertension. Based on recent studies it has become increasingly clear that the vasculature is itself a complex, integrated organ capable of autonomous generation of locally active factors that mediate changes in tone and structure. This review will examine the implications of this new molecular vascular biology paradigm in hypertension research, focusing on five areas in which vascular biology has had or will have major effects on hypertension research: (1) the discovery of novel endogenous biologically active molecules synthesized by the vessel wall, (2) the elucidation of molecular mechanisms and consequences of vascular remodeling in hypertension, (3) an understanding of the developmental biology of the blood vessel and the relation to pathobiology, (4) the in vivo testing of in vitro hypotheses using in vivo gene transfer, and (5) the development of novel treatment strategies based on vascular molecular biology, such as gene therapy.

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“…In neonatal rat cardiac cardiomyocytes, exogenous TGF-β sustained spontaneous rhythmic beating in serum-free conditions (20); however, the in vivo relevance of these observations is unclear.…”

Section: Expression Of Tgf-β In Normal Myocardiummentioning

confidence: 97%

The role of transforming growth factor (TGF)-β in the infarcted myocardium

Frangogiannis

2017

J. Thorac. Dis.

119

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The adult mammalian heart has negligible regenerative capacity. Following myocardial infarction, sudden necrosis of cardiomyocytes triggers an intense inflammatory reaction that clears the wound from dead cells and matrix debris, while activating a reparative program. A growing body of evidence suggests that members of the transforming growth factor (TGF)-β family critically regulate the inflammatory and reparative response following infarction. Although all three TGF-β isoforms (TGF-β1, -β2 and -β3) are markedly upregulated in the infarcted myocardium, information on isoform-specific actions is limited.Experimental studies have suggested that TGF-β exerts a wide range of actions on cardiomyocytes, fibroblasts, immune cells, and vascular cells. The findings are often conflicting, reflecting the contextdependence of TGF-β-mediated effects; conclusions are often based exclusively on in vitro studies and on associative evidence. TGF-β has been reported to modulate cardiomyocyte survival responses, promote monocyte recruitment, inhibit macrophage pro-inflammatory gene expression, suppress adhesion molecule synthesis by endothelial cells, promote myofibroblast conversion and extracellular matrix synthesis, and mediate both angiogenic and angiostatic effects. This review manuscript discusses our understanding of the cell biological effects of TGF-β in myocardial infarction. We discuss the relative significance of downstream TGF-β-mediated Smad-dependent and -independent pathways, and the risks and challenges of therapeutic TGF-β targeting. Considering the high significance of TGF-β-mediated actions in vivo, study of cell-specific effects and dissection of downstream signaling pathways are needed in order to design safe and effective therapeutic approaches.

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Role of transforming growth factor-beta in maintenance of function of cultured neonatal cardiac myocytes. Autocrine action and reversal of damaging effects of interleukin-1.

Cited by 93 publications

References 42 publications

Transforming Growth Factor-β Function Blocking Prevents Myocardial Fibrosis and Diastolic Dysfunction in Pressure-Overloaded Rats

Transforming Growth Factor-β Function Blocking Prevents Myocardial Fibrosis and Diastolic Dysfunction in Pressure-Overloaded Rats

New perspectives in hypertension research. Potentials of vascular biology.

The role of transforming growth factor (TGF)-β in the infarcted myocardium

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