Expression of Endothelin-1, Endothelin-Converting Enzyme, and Endothelin Receptors in Chronic Heart Failure

Zolk, Oliver; Quattek, Jessika; Sitzler, Gerhard; Schrader, Thomas O.; Nickenig, Georg; Schnabel, Petra; Shimada, Kohei; Takahashi, Masaaki; Böhm, Michael

doi:10.1161/01.cir.99.16.2118

Cited by 174 publications

(99 citation statements)

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“…Furthermore, one has to bear in mind that the ET B R was upregulated in ETϩ/ϩeNOSϪ/Ϫ mice. It is widely known that the ET B R acts as a clearance receptor for ET-1; therefore, regulation or pharmacologic intervention at the ET B R was shown to have an impact on ET-1 levels (6,7,43,44). Furthermore ET-1 is known to exhibit high affinity to its receptors.…”

Section: Discussionmentioning

confidence: 99%

Lack of Endothelial Nitric Oxide Synthase Promotes Endothelin-Induced Hypertension

Quaschning

Voß

Relle

et al. 2007

Journal of the American Society of Nephrology

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Endothelin-1 (ET-1) is one of the most potent biologic vasoconstrictors. Nevertheless, transgenic mice that overexpress ET-1 exhibit normal BP. It was hypothesized that vascular effects of ET-1 may be antagonized by an increase of the endothelial counterpart of ET-1, nitric oxide (NO), which is produced by the endothelial NO synthase (eNOS). Therefore, cross-bred animals of ET transgenic mice (ET؉/؉) and eNOS knockout (eNOS؊/؊) mice and were generated, and BP and endothelial function were evaluated in these animals. Endothelium-dependent and -independent vascular function was assessed as relaxation/contraction of isolated preconstricted aortic rings. The tissue ET and NO system was determined in aortic rings by quantitative real-time PCR and Western blotting. Systolic BP was similar in ET؉/؉ and wild-type (WT) mice but was significantly elevated in eNOS؊/؊ mice (117 ؎ 4 mmHg versus 94 ؎ 6 mmHg in WT mice; P < 0.001) and even more elevated in ET؉/؉ eNOS؊/؊ cross-bred mice (130 ؎ 4 mmHg; P < 0.05 versus eNOS؊/؊). Maximum endothelium-dependent relaxation was enhanced in ET؉/؉ mice (103 ؎ 6 versus 87 ؎ 4% of preconstriction in WT littermates; P < 0.05) and was completely blunted in eNOS؊/؊ (؊3 ؎ 4%) and ET؉/؉ eNOS؊/؊ mice (؊4 ؎ 4%), respectively. Endothelium-independent relaxation was comparable among all groups. T he intact endothelium produces a variety of vasoactive substances, such as nitric oxide (NO), thromboxane, and the 21-amino acid peptide endothelin-1 (ET-1). ET-1 is a potent vasoconstrictor (1) and mitogen in vivo and in vitro and exerts its biologic effects via activation of specific receptors: Whereas on vascular smooth muscle cells the predominant ET receptor is the ET A receptor (ET A R) subtype (2,3), contributing to long-lasting vasoconstriction, endothelial cells express the ET B receptor (ET B R), mediating the formation of NO (4) and prostacyclin (5) and featuring the pulmonary clearance of circulating ET-1 (6) as well as the reuptake of ET-1 by endothelial cells (7).Correspondingly, intravenous administration of ET-1 causes a rapid and transient vasodilation followed by a sustained increase in BP (8). In addition to the negative feedback loop via ET B R, ET-1 production in the vascular wall is inhibited by NO (9) and prostacyclin (10) via cGMP-dependent mechanisms. Therefore, the NO system may be considered as the functional counterpart of the ET system (11-16), thus warranting the sub-

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Section: Discussionmentioning

confidence: 99%

Lack of Endothelial Nitric Oxide Synthase Promotes Endothelin-Induced Hypertension

Quaschning

Voß

Relle

et al. 2007

Journal of the American Society of Nephrology

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“…An increase of ETA receptor density was also reported for heart failure in cardiomyopathic hamsters, 22 chronic heart failure due to myocardial infarction in rats, 17 and end-stage heart failure due to dilated cardiomyopathy in humans. 23 Thus, the transition from compensatory LVH in hypertensive Ren2-10 rats to mainly diastolic dysfunction in older Ren2 rats is paralleled by an activation of all components of the cardiac ET system.…”

Section: Activation Of Cardiac Et System Parallels Transition To LV Dmentioning

confidence: 98%

Cardiac Endothelin System Impairs Left Ventricular Function in Renin-Dependent Hypertension via Decreased Sarcoplasmic Reticulum Ca ²⁺ Uptake

Rothermund

Pinto²,

Hocher

et al. 2000

Circulation

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Background-We evaluated the role of the cardiac endothelin (ET) system in compensated hypertensive left ventricular (LV) hypertrophy (LVH) and after the transition toward LV dysfunction. Methods and Results-Hypertensive transgenic rats overexpressing the Ren2 gene (Ren2 rats) were investigated between the ages of 10 and 30 weeks (Ren2-10 and Ren2-30 groups, respectively) and compared with age-matched normotensive Sprague-Dawley (SD) rats (SD-10 and SD-30 groups, respectively). Systolic blood pressure and LV weight were elevated in both Ren2 groups compared with their age-matched SD control groups (PϽ0.0001). In Ren2-30 rats, LV end-diastolic pressure increased and ϪdP/dt max decreased compared with the values in SD-30 and Ren2-10 rats (PϽ0.05). This was paralleled by an activation of LV mRNA expression of preproET-1 and ET-converting enzyme-1 and ET subtype A (ETA) receptor binding in Ren2-30 compared with Ren2-10 rats (PϽ0.001). Cardiac fibrosis was increased and sarcoplasmic reticulum (SR) Ca 2ϩ reuptake was reduced in Ren2-30 compared with SD-30 and Ren2-10 rats (PϽ0.05). Treatment of Ren2 rats with the selective ETA receptor antagonist Lu135252 between 10 and 30 weeks of age did not lower systolic blood pressure, heart weight, or cardiac fibrosis but completely prevented the deterioration of LV end-diastolic pressure and abolished alterations in ϪdP/dt max and SR Ca 2ϩ reuptake compared with no treatment in Ren2-30 and SD-30 rats (PϽ0.05). Conclusions-Activation of the cardiac ET system accounts at least in part for the LV dysfunction that gradually develops in LVH. The protective effect of ETA antagonism can be attributed to the improvement of diastolic LV function that is due to normalization of impaired SR Ca 2ϩ uptake. (Circulation. 2000;102:1582-1588.)

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“…ET A receptors are upregulated in heart failure, whereas the ET B receptor appears to be downregulated. 39,40 Both intravenous and oral ET receptor antagonists have been studied for acute and chronic heart failure ( Table 2). The nonselective ET receptor antagonist tezosentan was studied in the RITZ Trials (Randomized Intravenous TeZosentan), which consisted of 4 phase III studies of tezosentan, run in parallel, in patients with acute heart failure requiring hospitalization.…”

Section: Congestive Heart Failurementioning

confidence: 99%

Endothelin Receptor Blockers in Cardiovascular Disease

Rich¹,

McLaughlin²

2003

Circulation

199

126

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Abstract-The endothelin (ET) system is comprised of 4 active ETs, with ET-1 being the predominant isoform in the cardiovascular system. Because of the potent vasoconstricting and mitogenic effects of ET-1 and its involvement in various cardiovascular diseases, blockade of the ET receptor has received considerable attention. ET receptor antagonism has been demonstrated to be beneficial in patients with pulmonary hypertension. The nonselective ET receptor antagonist bosentan improves exercise capacity and increases time to clinical worsening in patients with pulmonary arterial hypertension. Key Words: endothelin Ⅲ heart failure Ⅲ pulmonary heart disease T he endothelin (ET) system, like other vascular regulatory systems, consists of a parent peptide that undergoes enzymatic activation and exerts its biologic effects by modulating specific receptors. Of the 4 active ETs (ET 1 through 4), ET-1 is the predominant isoform in the cardiovascular system, which is generated through the cleavage of prepro ET-1 to big ET-1 and then to ET-1 by the action of ET-converting enzymes. ET-1 is found in endothelial cells and is released toward the vascular smooth muscle consistent with a paracrine role, but it is also produced by smooth muscle cells and cardiomyocytes. 1,2 ET-1 has vasoconstrictive and mitogenic effects, stimulates the production of growth factors such as vascular endothelial growth factor and basic fibroblast growth factor, and potentiates the effects of transforming growth factor-␤ and platelet-derived growth factor. 3-7 Chronic ET-1 stimulation can result in myocardial fibrosis and hypertrophy and vascular fibrosis with extracellular matrix proliferation. 8 In the lung, ET-1 is abundantly expressed in the pulmonary vasculature and appears to play an important role in the regulation of pulmonary vascular tone. 9 ET-1 is also produced in leukocytes where it influences the production of a wide range of cytokines in the inflammatory response. 10 ET is regulated in an autocrine fashion by physiochemical factors such as blood flow, pulsatile stretch, sheer stress, and pH. 11-13 Acute hypoxia leads to selective stimulation of the ET-1 gene and ET synthesis in the pulmonary vasculature. 14 ET-1 biosynthesis is also stimulated by low-density lipoprotein cholesterol and glucose, and thrombin. 15,16 Endogenous inhibitors of ET-1 synthesis include nitric oxide, prostacyclin, atrial natriuretic peptides, and estrogens. [17][18][19][20] ET-1 exerts its major vascular effects through activation of 2 distinct G protein coupled ET A and ET B receptors. ET A receptors are found in the medial smooth muscle layers of the blood vessels, and atrial and ventricular myocardium. 21 When stimulated, the ET A receptors induce vasoconstriction and cellular proliferation by increasing intracellular calcium.ET B receptors are localized on endothelial cells and, to some extent, smooth muscle cells and macrophages. 22 The activation of ET B receptors stimulates the release of nitric oxide and prostacyclin and prevents apoptosis. 23 Normally, t...

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Expression of Endothelin-1, Endothelin-Converting Enzyme, and Endothelin Receptors in Chronic Heart Failure

Cited by 174 publications

References 25 publications

Lack of Endothelial Nitric Oxide Synthase Promotes Endothelin-Induced Hypertension

Lack of Endothelial Nitric Oxide Synthase Promotes Endothelin-Induced Hypertension

Cardiac Endothelin System Impairs Left Ventricular Function in Renin-Dependent Hypertension via Decreased Sarcoplasmic Reticulum Ca ²⁺ Uptake

Endothelin Receptor Blockers in Cardiovascular Disease

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Expression of Endothelin-1, Endothelin-Converting Enzyme, and Endothelin Receptors in Chronic Heart Failure

Cited by 174 publications

References 25 publications

Lack of Endothelial Nitric Oxide Synthase Promotes Endothelin-Induced Hypertension

Lack of Endothelial Nitric Oxide Synthase Promotes Endothelin-Induced Hypertension

Cardiac Endothelin System Impairs Left Ventricular Function in Renin-Dependent Hypertension via Decreased Sarcoplasmic Reticulum Ca 2+ Uptake

Endothelin Receptor Blockers in Cardiovascular Disease

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Cardiac Endothelin System Impairs Left Ventricular Function in Renin-Dependent Hypertension via Decreased Sarcoplasmic Reticulum Ca ²⁺ Uptake