Endothelin-Converting Enzyme Inhibition Ameliorates Angiotensin II–Induced Cardiac Damage

Müller, Dominik N.; Mullally, Alexander; Dechend, Ralf; Park, Joon-Keun; Fiebeler, Anette; Pilz, Bernhard; Löffler, Bernd–Michael; Blum‐Kaelin, Denise; Masur, Stefan; Dehmlow, Henrietta; Aebi, Johannes D.; Haller, Hermann; Luft, Friedrich C.

doi:10.1161/01.hyp.0000039748.88581.a0

Cited by 32 publications

(27 citation statements)

References 32 publications

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“…59 In rats transgenic for both the human renin and human angiotensinogen genes, bosentan inhibited the activation of both nuclear factor-kappa B and transcription factor activator protein in the kidney and heart. 60 Furthermore, inhibition of the endothelin-converting enzyme reduced mortality and ameliorated cardiac damage in this model. 60 In animal models of mineralocorticoid-induced hypertension, changes in vascular wall structure and expression of extracellular matrix proteins can be prevented by ET receptor blockade.…”

Section: Et-1 In Vascular Remodelingmentioning

confidence: 83%

“…60 Furthermore, inhibition of the endothelin-converting enzyme reduced mortality and ameliorated cardiac damage in this model. 60 In animal models of mineralocorticoid-induced hypertension, changes in vascular wall structure and expression of extracellular matrix proteins can be prevented by ET receptor blockade. 27,32,61,62 …”

Section: Et-1 In Vascular Remodelingmentioning

confidence: 99%

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Endothelin, Angiotensin, and Oxidative Stress in Hypertension

Pollock

2005

Hypertension

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E ndothelin (ET)-1 is a potent vasoconstrictor and mitogen, and because of these properties, it is thought to play a role in the development of hypertension. 1,2 The vascular endothelium is a major source of ET-1 production, although a variety of other cell types also have been shown to synthesize and release ET-1. ET-1 is believed to act in a paracrine manner on ET A and ET B receptors on smooth muscle, which mediate contraction, cell proliferation, and hypertrophy. Activation of ET B receptors on endothelial cells stimulates the production of prostacyclin and nitric oxide to induce vasorelaxation and inhibition of sodium transport in renal tubules. Given these properties, considerable attention has been paid to the mechanisms of ET-1 action as it relates to the renal control of blood pressure and the pathogenesis of salt-dependent hypertension. Renal ET synthesis is increased in experimental animals maintained on a high-salt diet and ET A receptor antagonists lower arterial pressure primarily in salt-dependent models of hypertension. 1,2 For the past 30 to 40 years, the actions of angiotensin (Ang) II has been arguably the most widely investigated factor in hypertension research. Although physiology textbooks agree on the major actions of Ang II, eg, vasoconstriction and release of aldosterone, recent attention has focused on its ability to stimulate the synthesis of ET-1, 3-5 as well as reactive oxygen species. 6 There are many reactive oxygen species such as superoxide, hydroxyl radical, and hydrogen peroxide that are produced by all cell types and can have profound effects on the vascular system to impact blood pressure regulation. Most recent attention has been paid to the role of superoxide. There are many enzymatic sources of superoxide including NADPH oxidase, xanthine oxidase, nitric oxide synthase, and cytochrome P450. The focus of the current review, however, is be on the interaction between the 2 peptide systems, ET-1 and Ang II, as they relate to oxidative stress. ET-1 in Ang II Hypertension ET-1 and Oxidative StressThe clinical significance of oxidative stress and its role in hypertension was recently reviewed by Touyz, 18 and so the current discussion is limited to the interaction between ET-1, Ang II, and superoxide.Studies from Ortiz et al have shown that the slow pressor response to Ang II is associated with increases in ET, as well as isoprostanes, a marker of lipid oxidation and an index of oxidative stress. 9 These effects could be prevented with bosentan, suggesting a role for ET in mediating the increase in oxidative stress in this model. They went on to demonstrate that antioxidant treatment with the superoxide dismutase mimetic, tempol, or the combination of vitamins C and E reduced Ang II-induced changes in ET expression. 14 Acute administration of tempol also has antihypertensive effects in rats chronically infused with Ang II. 15 Long-term treatment with tempol will lower arterial pressure in several models of hypertension associated with increases in ET production, including chroni...

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Section: Et-1 In Vascular Remodelingmentioning

confidence: 83%

Section: Et-1 In Vascular Remodelingmentioning

confidence: 99%

Endothelin, Angiotensin, and Oxidative Stress in Hypertension

Pollock

2005

Hypertension

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“…Experimental and clinical observations indicate that Ang II stimulation induces hypertension (38,39), pathological cardiac remodeling (40,41), and heart failure (42,43). When Ang II stimulation causes pressure or volume overload of the heart, the resulting cardiac hypertrophy is initially a compensatory response to preserve cardiac performance against cardiac load.…”

Section: Discussionmentioning

confidence: 99%

Androgen Receptor Gene Knockout Male Mice Exhibit Impaired Cardiac Growth and Exacerbation of Angiotensin II-induced Cardiac Fibrosis

Ikeda¹,

Aihara²,

Satō

et al. 2005

Journal of Biological Chemistry

132

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Androgen has anabolic effects on cardiac myocytes and has been shown to enhance left ventricular enlargement and function. However, the physiological and patho-physiological roles of androgen in cardiac growth and cardiac stress-induced remodeling remains unclear. We aimed to clarify whether the androgen-nuclear androgen receptor (AR) system contributes to the cardiac growth and angiotensin II (Ang II)-stimulated cardiac remodeling by using systemic AR-null male mice. AR knock-out (ARKO) male mice, at 25 weeks of age, and age-matched wild-type (WT) male mice were treated with or without Ang II stimulation (2.0 mg/kg/day) for 2 weeks. ARKO mice with or without Ang II stimulation showed a significant reduction in the heart-to-body weight ratio compared with those of WT mice. In addition, echocardiographic analysis demonstrated impairments of both the concentric hypertrophic response and left ventricular function in Ang II-stimulated ARKO mice. Western blot analysis of the myocardium revealed that activation of extracellular signal-regulated kinases (ERK) 1/2 and ERK5 by Ang II stimulation were lower in ARKO mice than those of WT mice. Ang II stimulation caused more prominent cardiac fibrosis in ARKO mice than in WT mice with enhanced expression of types I and III collagen and transforming growth factor-␤1 genes and with increased Smad2 activation. These results suggest that, in male mice, the androgen-AR system participates in normal cardiac growth and modulates cardiac adaptive hypertrophy and fibrosis during the process of cardiac remodeling under hypertrophic stress.Androgen exerts a variety of biological effects in many target organs, including male genitalia, brain, and skeletal tissues (1, 2). Most of these actions are mediated through the transcriptional control of particular sets of target genes by the nuclear androgen receptor (AR).1 AR is a ligand-inducible transcription factor that belongs to the nuclear receptor superfamily (3, 4). Upon hormone binding, AR is translocated from the cytosol into the nucleus where it binds specific promoter elements. A number of coregulators and/or coregulator complexes are then recruited to AR, which then activates or represses the transcription of various target genes (2, 3, 5-7). To clarify the physiological function of androgen via AR transcriptional regulation, we generated AR knock-out (ARKO) mice by means of the Cre-loxP system and have reported that ARKO male mice manifest late-onset obesity (8), high turnover osteopenia (9), and impaired brain masculinization (10).In addition to the classic target tissues of androgens, the AR gene is also expressed in mammalian cardiomyocytes, suggesting that androgens may play a role in the heart (11). In fact, Marsh and colleagues (11) have shown that androgens produce cardiac hypertrophy by a direct, receptor-specific mechanism. They also revealed that androgens regulate functional expression of an L-type calcium channel in isolated rat ventricular myocytes, leading to a modulation of cardiac performance in males (12). Li et a...

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“…Therefore, combining the results of our present study with the previously published studies (7,26,27,33), we can speculate that PKC, NF-B, and AP-1 can control both upstream and downstream effector molecules in the high glucose-induced signaling pathway. However, the role of ET receptor-mediated signaling in diabetes leading to NF-B activation may potentially be influenced by other factors (31), which remain to be investigated.…”

Section: Discussionmentioning

confidence: 99%

“…ET-1 activates NF-B in the hepatic stellate cells via the ET B receptor (16). Angiotensin II-induced end organ damage in hypertension has been shown to be mediated via ET receptor-dependent NF-B and AP-1 activation (31). Various pathways of tissue injury caused by hyperglycemia in vivo or high glucose concentration in cell cultures may activate transcription factors such as NF-B and AP-1 and subsequently alter the expression of several genes important in the pathogenesis of diabetic complications (30,32,33).…”

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confidence: 99%

Differential activation of NF-κB and AP-1 in increased fibronectin synthesis in target organs of diabetic complications

Chen

Khan

Cukiernik

et al. 2003

American Journal of Physiology-Endocrinology and Metabolism

145

154

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Increased extracellular matrix protein production leading to structural abnormalities is a characteristic feature of chronic diabetic complications. We previously showed that high glucose in endothelial cell culture leads to the upregulation of basement membrane protein fibronectin (FN) via an endothelin (ET)-dependent pathway involving activation of NF-κB and activating protein-1 (AP-1). To delineate the mechanisms of basement membrane thickening, we used an animal model of chronic diabetes and evaluated ET-dependent activation of NF-κB and AP-1 and subsequent upregulation of FN in three target organs of chronic diabetic complications. After 3 mo of diabetes, retina, renal cortex, and myocardium demonstrated increased FN mRNA and increased ET-1 mRNA expression. Increased FN expression was shown to be dependent on ET receptor-mediated signaling, as the increase was prevented by the dual ET receptor antagonist bosentan. NF-κB activation was most pronounced in the retina, followed by kidney and heart. AP-1 activation was also most pronounced in the retina but was similar in both kidney and heart. Bosentan treatment prevented NF-κB activation in the retina and heart and AP-1 activation in the retina and kidney. These data indicate that, although ETs are important in increased FN production due to diabetes, the mechanisms with respect to transcription factor activation may vary depending on the microenvironment of the organ.

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Endothelin-Converting Enzyme Inhibition Ameliorates Angiotensin II–Induced Cardiac Damage

Cited by 32 publications

References 32 publications

Endothelin, Angiotensin, and Oxidative Stress in Hypertension

Endothelin, Angiotensin, and Oxidative Stress in Hypertension

Androgen Receptor Gene Knockout Male Mice Exhibit Impaired Cardiac Growth and Exacerbation of Angiotensin II-induced Cardiac Fibrosis

Differential activation of NF-κB and AP-1 in increased fibronectin synthesis in target organs of diabetic complications

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