Transforming Growth Factor β1 Oppositely Regulates the Hypertrophic and Contractile Response to β-Adrenergic Stimulation in the Heart

Huntgeburth, Michael; Tiemann, Klaus; Shahverdyan, Robert; Schlüter, Klaus‐Dieter; Schreckenberg, Rolf; Groß, Marie-Luise; Mödersheim, Sonja; Caglayan, Evren; Müller‐Ehmsen, Jochen; Ghanem, Alexander; Vantler, Marius; Zimmermann, Wolfram H.; Böhm, Michael; Rosenkranz, Stephan

doi:10.1371/journal.pone.0026628

Cited by 46 publications

(31 citation statements)

References 46 publications

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“…In terms of the activated fibroblast within the MI, the myoFB, this appears to be a TGF dependent process; therefore, strategies that disrupt TGF signaling are likely to alter this fibroblast transdifferentiation process. [14-18,94-96] For instance, membrane bound MMPs likely contribute to the activation of TGF within the ECM, and this proteolytic-activation cascade may yield a potential target. [18] In other studies, direct interference with TGF by genetic, neutralizing antibodies or oral pharmacological inhibitors have demonstrated early favorable results in animal models of HFrEF.…”

Section: Therapeuticsmentioning

confidence: 99%

Integrating the Myocardial Matrix Into Heart Failure Recognition and Management

Spinale

Zile

2013

Circulation Research

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In contrast to public perception, the morbidity and mortality as well as the resultant health care costs associated with chronic heart failure (HF) are increasing and arguably reaching epidemic proportions. While basic research efforts have provided unique insights into fundamental processes that govern myocardial extracellular matrix (ECM) growth and function, the translation of these findings to improved diagnostics and therapeutics for HF have not been as forthcoming. The factors that contribute to this relative paucity of new clinical tools for HF are multifactorial but likely include the need to recognize and differentiate HF phenotypes, and to couple the use of biomarkers and multimodality imaging in early translational research studies. Recognizing the classification scheme of HF with a reduced ejection fraction (HFrEF) to that of HF with a preserved ejection fraction (HFpEF)and incorporating unique and differential measurements of ECM remodeling to these specific disease processes are warranted. For example, profiling pathways of ECM degradation such as the matrix metalloproteinases (MMPs) in patients with ischemic heart disease and HFrEF can provide prognostic information in terms of risk of progression to HF. In patients with chronic hypertensive disease and HFpEF, plasma profiling indices of ECM synthesis and turnover, as well as advances in ECM imaging have been shown to provide diagnostic and prognostic utility. In terms of therapeutics, strategies which stabilize the ECM in HFrEF hold potential, whereas in contradistinction, selective antifibrotic agents may hold promise with HFpEF.

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Section: Therapeuticsmentioning

confidence: 99%

Integrating the Myocardial Matrix Into Heart Failure Recognition and Management

Spinale

Zile

2013

Circulation Research

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“…Other investigations using models of cutaneous, pulmonary, and renal fibrosis suggested crucial fibrogenic actions of Smad-independent cascades 10,11 . In addition to its pro-fibrotic actions, TGF-β may also contribute to the development of cardiac hypertrophy, acting downstream of angiotensin II 12 . Induction and activation of TGF-β is consistently found in diabetic tissues and has been implicated in the pathogenesis of organ dysfunction; stimulation of TGF-β signaling pathways is associated with cardiac fibrosis in experimental models of type 1 13 and type 2 diabetes 14 .…”

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confidence: 99%

Smad3 Signaling Promotes Fibrosis While Preserving Cardiac and Aortic Geometry in Obese Diabetic Mice

Biernacka

Cavalera

Wang

et al. 2015

Circ: Heart Failure

104

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Background Heart failure in diabetics is associated with cardiac hypertrophy, fibrosis and diastolic dysfunction. Activation of transforming growth factor (TGF)-β/Smad3 signaling in the diabetic myocardium may mediate fibrosis and diastolic heart failure, while preserving matrix homeostasis. We hypothesized that Smad3 may play a key role in the pathogenesis of cardiovascular remodeling associated with diabetes and obesity. Methods and Results We generated leptin-resistant db/db Smad3 null mice (dbSKO) and db/db Smad3 +/- animals (dbShet). Smad3 haploinsufficiency did not affect metabolic function in db/db mice, but protected from myocardial diastolic dysfunction, while causing left ventricular chamber dilation. Improved cardiac compliance and chamber dilation in dbShet animals was associated with decreased cardiomyocyte hypertrophy, reduced collagen deposition and accentuated matrix metalloproteinase (MMP) activity. Attenuation of hypertrophy and fibrosis in dbShet hearts was associated with reduced myocardial oxidative and nitrosative stress. dbSKO mice had reduced weight gain and decreased adiposity associated with attenuated insulin resistance, but also exhibited high early mortality, in part due to spontaneous rupture of the ascending aorta. Ultrasound studies showed that both lean and obese Smad3 null animals had significant aortic dilation. Aortic dilation in dbSKO mice occurred despite reduced hypertension, and was associated with perturbed matrix balance in the vascular wall. Conclusions Smad3 mediates diabetic cardiac hypertrophy, fibrosis and diastolic dysfunction, while preserving normal cardiac geometry and maintaining the integrity of the vascular wall.

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“…Mechanism of heart affection in these types of diseases is the left ventricular wall remodeling due to an increased activation of TGF-β signaling pathway. Huntgeburt et al (14) demonstrate that TGF-β regulates the hypertrophic and contractile response to β-adrenergic stimulation in the heart, leading to cardiac hypertrophy and myocardial dysfunction. Circulating TGF-β has received attention because it may potentially serve as a biomarker for of aortic remodeling progression in patients not only with MS but also in other genetic aortic syndromes (15,16).…”

Section: Discussionmentioning

confidence: 99%

Cardiomyopathy in patients with Marfan syndrome and marfanoid habitus

Лунева¹,

Малев²,

Korshunova³

et al. 2017

Curr Res Cardiol

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MSis one of the most common heritable disorder of connective tissue. In the range of MS complications are aortic aneurism, mitral valve prolapses and myocardial dysfunction (1). MS manifestations caused by mutations of fibrillin-1, a structural component of extracellular matrix, and also violation of the regulation of transforming growth factor-β. A number of studies (2,3) showed that excessive activation of TGF-β signaling pathway is the main reason of the impairment of LV function and aorta pathology in MS. Deterioration of systolic and diastolic function and enlargement of LV dimensions was found in patients with MS regardless the absence of hemodynamic overload due to mitral or aortic regurgitation in presence of mitral valve prolapse or aortic dilatation. The term "Marfan cardiomyopathy" is used to indicate changes in left ventricular function in the absence of significant valvular pathology in MS (4,5). In spite the fact that cardiomyopathy in MS is well studied it is still unknown if there are changes in the cardiac function in patients with similar connective tissue abnormality such as marfanoid habitus. marfanoid habitus includes arachnodactyly, long hands and feet, increased skin stretch, joint hypermobility and changes in the physiology of the pectus (Table 1). METHODS:In the study were included 98 persons -8 patients with Marfan syndrome, 24 with marfanoid habitus and 66 healthy subjects. Echocardiography was performed to all patients. Speckle tracking echocardiography was used to assess the left ventricular deformation indices. Concentrations of transforming growth factor-β1 and -β2 in serum were determined by enzyme-linked immunosorbent assay. RESULTS:Systolic left ventricular function was significantly lower in the Marfan syndrome group; as well global longitudinal left ventricular strain worsening was detected in MS group comparing to control group. In marfanoid habitus subjects, we found significant decrease of the circumferential strain in the interventricular septum and inferior wall. transforming growth factor-β1 and -β2 serum levels were elevated in patients with Marfan syndrome. Elevation of transforming growth factor-β1 was statistically nonsignificant unlike to transforming growth factor-β2 in the marfanoid habitus group. Negative correlations between the serum level of transforming growth factor-β2 and systolic radial strain in the marfanoid habitus group also have been found. CONCLUSION:Worsening of regional myocardial deformation may be the first sign of deterioration of the left ventricular systolic function and the existence of primary cardiomyopathy in asymptomatic marfanoid habitus patients, which could affect their long-term prognosis and may be caused by increased transforming growth factor-β signaling. Key Words: Marfan syndrome; Marfanoid habitus; Cardiomyopathy; Left ventricular systolic function; Myocardial deformation; Transforming growth factor-βMarfanoid features are present in several heritable disorders of connective tissue, mimicking some of the changes of Marfan syndr...

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Transforming Growth Factor β1 Oppositely Regulates the Hypertrophic and Contractile Response to β-Adrenergic Stimulation in the Heart

Cited by 46 publications

References 46 publications

Integrating the Myocardial Matrix Into Heart Failure Recognition and Management

Integrating the Myocardial Matrix Into Heart Failure Recognition and Management

Smad3 Signaling Promotes Fibrosis While Preserving Cardiac and Aortic Geometry in Obese Diabetic Mice

Cardiomyopathy in patients with Marfan syndrome and marfanoid habitus

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