Endothelin-1 is an autocrine/paracrine factor in the mechanism of angiotensin II-induced hypertrophy in cultured rat cardiomyocytes.

Itoh, Hiroshi; Hirata, Yukio; Adachi, Susumu; Tanaka, Masato; Tsujino, Motoyoshi; Koike, Atsushi; Nogami, Akihiko; Murumo, F; Hiroe, Michiaki

doi:10.1172/jci116579

Cited by 528 publications

(308 citation statements)

References 29 publications

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“…The effects of Ang II on fibrillar collagen synthesis are principally mediated through TGF␤ 1 and endothelin-1 (ET-1). [13][14][15][16] Whether or not Ang II induces CTGF gene expression is currently unknown. Ang II may also regulate collagen degradation by attenuating matrix metalloproteinase activities, and by enhancing the production of TIMP-1.…”

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confidence: 99%

Angiotensin II Induces Connective Tissue Growth Factor Gene Expression via Calcineurin-Dependent Pathways

Finckenberg

Inkinen

Ahonen

et al. 2003

The American Journal of Pathology

102

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Connective tissue growth factor (CTGF) is a polypeptide implicated in the extracellular matrix synthesis.Previous studies have provided evidence that angiotensin II (Ang II) promotes collagen synthesis and regulates collagen degradation. We investigated whether or not CTGF mediates the profibrotic effects of Ang II in the heart and kidneys and the role of calcineurin-dependent pathways in CTGF gene regulation. In transgenic rats harboring human renin and angiotensinogen genes, Ang II induced an age-dependent increase in myocardial CTGF expression, which was 3.5-fold greater compared to normotensive Sprague Dawley (SD) rats. CTGF overexpression correlated closely with the Ang II-induced rise in blood pressure. CTGF mRNA and protein were located predominantly in areas with leukocyte infiltration, myocardial, and vascular lesions and co-localized with TGF␤ 1 , collagen I, and collagen III mRNA expressions. Ang II induced CTGF mRNA and protein to a lesser extent in the kidneys, predominantly in glomeruli, arterioles, and in the interstitium with ample inflammation. However, no expression was found in the right ventricle or pulmonary arteries. Blockade of calcineurin activity by cyclosporine A completely normalized Ang II-induced CTGF overexpression in heart and kidney, suppressed the inflammatory response, and mitigated Ang II-induced cell proliferation and apoptosis. In contrast, blockade of mTOR (target of rapamycin) pathway by everolimus, further increased the expression of CTGF even though everolimus ameliorated cell proliferation and T-cellmediated inflammation. Our findings provide evidence that CTGF mediates Ang II-induced fibrosis in the heart and kidneys via blood pressure and cal-

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mentioning

confidence: 99%

Angiotensin II Induces Connective Tissue Growth Factor Gene Expression via Calcineurin-Dependent Pathways

Finckenberg

Inkinen

Ahonen

et al. 2003

The American Journal of Pathology

102

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“…Wall stretch, 11 ischemia, 12 and angiotensin II are some pathophysiologically important stimuli that can trigger its production. 13 Cardiomyocytes express mostly ET A receptors. In cardiac fibroblasts, a mixed population of ET A and ET B receptors can be found.…”

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confidence: 99%

Role of endothelin-1 in hypertension

Iglarz

Schiffrin

2003

Current Science Inc

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Abstract-Endothelin-1 (ET-1) is overexpressed in the vascular wall in certain models of experimental hypertension:deoxycorticosterone acetate salt-treated rats, deoxycorticosterone acetate salt-treated spontaneously hypertensive rats (SHR), stroke-prone SHR, Dahl salt-sensitive rats, angiotensin II-infused rats, and 1-kidney 1 clip Goldblatt rats; it is not overexpressed in SHR, 2-kidney 1-clip hypertensive rats, or L-NAME-treated rats. In hypertensive rats without generalized vascular overexpression, however, expression of ET-1 was often enhanced in intramyocardial coronary arteries, suggesting a role of endothelin in myocardial ischemia in hypertension. In rats overexpressing ET-1, ET A/B and ET A -selective receptor antagonists lowered blood pressure and reduced vascular growth, particularly in small arteries, beyond what could be attributed to blood pressure lowering, suggesting a direct effect of ET-1 on growth. Hypertensive rats treated with endothelin antagonists are protected from stroke and renal injury. The ET A/B antagonist bosentan induced blood-pressure reductions in mildly hypertensive patients similar to those achieved with an angiotensinconverting enzyme inhibitor. Moderately to severely hypertensive patients presented with enhanced expression of prepro-ET-1 mRNA in the endothelium of subcutaneous resistance arteries, suggesting that these stages of hypertension may respond particularly well to endothelin antagonism. Hypertensive patients with coronary artery disease have increased arterial expression of ET-1, and increased plasma levels of immunoreactive endothelin have been described in black patients. ET-1 plays an important role in atherosclerosis, for which hypertension is an important risk factor. T he endothelins are potent 21-amino acid vasoconstrictor peptides encoded by 3 genes and produced in many different tissues, particularly the endothelium of blood vessels. 1,2 Endothelin-1 (ET-1), the main endothelin generated in the endothelium, acts in a paracrine or autocrine manner on ET A and ET B receptors on adjacent endothelial or smoothmuscle cells. The genes for ET A and ET B receptors have been cloned. 3,4 ET A and ET B receptors on smooth muscle induce contraction and stimulate proliferation and cell hypertrophy. 5 Endothelial ET B receptors stimulate the production of nitric oxide and prostacyclin and, accordingly, elicit vasorelaxation. 6 It is unclear whether the vasoconstrictor or vasorelaxant action of ET-1 is the predominant physiological effect. This may vary in different vascular beds.Mice in which the ET-1 gene has been inactivated exhibit a slight elevation of blood pressure, 7 which may result from hypoxemia resulting from the craniofacial developmental abnormalities that occur in this experimental paradigm or it may be an expression of a predominant vasodilator action of ET-1. A recent study evaluated this by using crosses of mice heterozygous for targeted disruption of the ET B receptor (Ϫ/ϩ) with mice homozygous for the piebald mutation of the ET B gene (s/s). 8 The prog...

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“…Endothelin-1 (ET-1) is a potent vasoconstrictor and proinflammatory peptide 30,31 normally secreted in a paracrine fashion from endothelial cells, 32 but can also be synthesized by macrophages. 33 In an excellent review, Boehm and Pernow 34 enumerate dozens of studies in which ET-1 is associated with endothelial dysfunction, inflammation and vasoconstriction, whereas blockade of ET-1 receptors leads to improved endothelial function with increased availability of NO.…”

Section: Serum Markersmentioning

confidence: 99%

Assessment of endothelial function in the patient with erectile dysfunction: an opportunity for the urologist

Tamler

Bar‐Chama

2008

Int J Impot Res

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Although there is now ample evidence that men with manifest coronary, cerebral and peripheral vascular disease and their risk factors are at highest risk for suffering from erectile dysfunction, recent findings demonstrate a strong connection between erectile dysfunction and endothelial dysfunction. This review explores how urologists and other providers may utilize the link between these conditions in clinical practice, compares methods of assessing endothelial dysfunction and finally speculates on how this additional information might impact treatment plans.

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Endothelin-1 is an autocrine/paracrine factor in the mechanism of angiotensin II-induced hypertrophy in cultured rat cardiomyocytes.

Cited by 528 publications

References 29 publications

Angiotensin II Induces Connective Tissue Growth Factor Gene Expression via Calcineurin-Dependent Pathways

Angiotensin II Induces Connective Tissue Growth Factor Gene Expression via Calcineurin-Dependent Pathways

Role of endothelin-1 in hypertension

Assessment of endothelial function in the patient with erectile dysfunction: an opportunity for the urologist

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