TGF- β1Downregulates PTHrP in Coronary Endothelial Cells

Wenzel, Sibylle; Schorr, Katja; Degenhardt, Heike; Frischkopf, Karen; Kojda, Georg; Wiesner, Rudolf J.; Rosenkranz, Stephan; Piper, Hans Michael; Klaus-Dieter, Klaus-Dieter

doi:10.1006/jmcc.2001.1382

Cited by 17 publications

(21 citation statements)

References 30 publications

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“…The hearts, lungs and PASMCs were homogenised and RNA was extracted according to the manufacturer's protocol (AGS, Heidelburg, Germany) in order to obtain total cellular RNA as described previously [21]. Aliquots (1 mg) were used for realtime PCR using the I-cycler (Biorad, Munich, Germany) and Syber-green as the fluorescence signal.…”

Section: Quantification Of Mrna Expressionmentioning

confidence: 99%

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Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension

Schermuly

Jp²,

Pullamsetti³

et al. 2008

Eur Respir J

218

168

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Alterations of the nitric oxide receptor, soluble guanylate cyclase (sGC) may contribute to the pathophysiology of pulmonary arterial hypertension (PAH). In the present study, the expression of sGC in explanted lung tissue of PAH patients was studied and the effects of the sGC stimulator BAY 63-2521 on enzyme activity, and haemodynamics and vascular remodelling were investigated in two independent animal models of PAH.Strong upregulation of sGC in pulmonary arterial vessels in the idiopathic PAH lungs compared with healthy donor lungs was demonstrated by immunohistochemistry. Upregulation of sGC was detected, similarly to humans, in the structurally remodelled smooth muscle layer in chronic hypoxic mouse lungs and lungs from monocrotaline (MCT)-injected rats. BAY 63-2521 is a novel, orally available compound that directly stimulates sGC and sensitises it to its physiological stimulator, nitric oxide. Chronic treatment of hypoxic mice and MCT-injected rats, with fully established PAH, with BAY 63-2521 (10 mg?kg) partially reversed the PAH, the right heart hypertrophy and the structural remodelling of the lung vasculature.Upregulation of soluble guanylate cyclase in pulmonary arterial smooth muscle cells was noted in human idiopathic pulmonary arterial hypertension lungs and lungs from animal models of pulmonary arterial hypertension. Stimulation of soluble guanylate cyclase reversed right heart hypertrophy and structural lung vascular remodelling. Soluble guanylate cyclase may thus offer a new target for therapeutic intervention in pulmonary arterial hypertension.KEYWORDS: BAY 63-2521, cardiovascular diseases, nitric oxide, pharmacology, pulmonary arterial hypertension, smooth muscle P ulmonary arterial hypertension (PAH) is a disabling disease, with high mortality, characterised by sustained elevation in pulmonary arterial pressure (Ppa) and pulmonary vascular remodelling due to proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) [1]. Imbalance of vasodilatory and vasoconstrictive mediators has been implicated in these changes. Reduced urinary excretion of prostaglandin (PG)I 2 and augmented excretion of thromboxane metabolites were found in patients with idiopathic PAH (IPAH) [2], and immunohistological studies have shown reduced expression of PGI 2 synthase in the pulmonary vessels originating from those patients [3]. Another important mediator in the regulation of vascular tone is nitric oxide (NO), which is synthesised by NO synthases. Local NO production from endothelium and epithelium regulates pulmonary perfusion, depending on alveolar ventilation to assure optimised ventilation/perfusion distribution [4][5][6]. In patients with IPAH, it has been reported that the expression of endothelial NO synthase is downregulated [7], while other reports show an upregulation in plexiform lesions of IPAH patients [8]. However, little is known about the expression and regulation of soluble guanylate cyclase (sGC) which operates as a receptor for NO. Typically, sGC is found as a hetero...

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Section: Quantification Of Mrna Expressionmentioning

confidence: 99%

“…DDCT is calculated by subtracting DCT of the experiment from DCT of the control. The primers used in the present study have been mentioned previously [21,22] and are listed in the online supplementary data. …”

Section: Quantification Of Mrna Expressionmentioning

confidence: 99%

Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension

Schermuly

Jp²,

Pullamsetti³

et al. 2008

Eur Respir J

218

168

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“…Nuclear localization of PTHrP has been shown to contribute to resistance against apoptosis in other cell types (Henderson et al, 1995). On endothelial cells, the growth inhibitor TGF-␤ 1 has been shown to induce endothelial apoptosis and down-regulate bcl-2 an antiapoptotic protein (Tsukada et al, 1995), and we could demonstrate that it decreased endothelial PTHrP expression (Wenzel et al, 2001). This correlation between the loss of PTHrP expression and the susceptibility to apoptosis suggests a causal relationship.…”

Section: Expression Of Pthrp In Coronary Endothelial Cells 115mentioning

confidence: 49%

“…Studies in PTHrP-deficient mice showed an absence of a normal zone of vascular invasion in developing cartilage (Karaplis and Kronenberg, 1996). We have recently shown that TGF-␤ 1 down-regulates PTHrP in coronary endothelial cells and inhibits endothelial cell proliferation (Taimor et al, 1999b;Wenzel et al, 2001). In contrast, phenylephrine increased the proliferation of coronary endothelial cells and PTHrP expression (as shown in this study).…”

Section: Expression Of Pthrp In Coronary Endothelial Cells 115mentioning

confidence: 99%

“…First, cardiac effects of PTHrP differ from systemic effects of PTHrP in circulation, because its effect on coronary resistance and cardiac function exceeds that of PTH in the rat heart (Nickols et al, 1989). Second, TGF-␤ 1 , a factor that plays an important role in the transition from hypertrophy to heart failure, down-regulates ventricular expression of PTHrP and causes a loss of ventricular PTHrP expression in spontaneously hypertensive rats that are stroke prone, which develop heart failure (Wenzel et al, 2001).…”

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Parathyroid Hormone-Related Peptide Is Induced by Stimulation of α_1A-Adrenoceptors and Improves Resistance against Apoptosis in Coronary Endothelial Cells

et al. 2003

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Parathyroid hormone-related peptide (PTHrP) is expressed throughout the vascular system, including coronary endothelial cells. The regulation of endothelial PTHrP expression and the role of PTHrP expression in endothelial cells is not clear. This study investigates the question of whether the stimulation of ␣-adrenergic or angiotensin II receptors increases endothelial expression of PTHrP and whether endogenously expressed PTHrP exerts intracrine effects in coronary endothelial cells. We found that the stimulation of ␣ 1A -adrenoceptors, but not that of angiotensin II, increases cellular expression of PTHrP in growing, but not in growth-arrested, coronary endothelial cells. Angiotensin II increases the expression of PTHrP in smooth muscle cells but not in endothelial cells. PTHrP enters the nucleus of endothelial cells at the stadium of confluence, which suggests an intracrine effect of PTHrP. It was further investigated whether the down-regulation of endogenous PTHrP expression by transfection with antisense oligonucleotides alters cell proliferation or apoptosis resistance in growing or nongrowing endothelial cells. Down-regulation of PTHrP did not modify cell proliferation, but it increased the amount of UV-induced apoptosis. An increased expression of PTHrP in cells pretreated with an ␣-adrenoceptor agonist reduced the basal rate of apoptosis and improved resistance against UV-induced apoptosis. These results indicate a novel intracrine effect of PTHrP in coronary endothelial cells that improves cell survival. In endothelial cells, its expression is regulated by ␣-adrenoceptor stimulation in a cell-cycle-dependent and cell-type-specific manner.

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Intrakrine, parakrine und autokrine Funktionen des PTH/PTHrP-Systems

Schlüter

Ross

2006

Molekularmedizinische Grundlagen Von Para- Und Autokrinen Regulationsstörungen

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TGF- β1Downregulates PTHrP in Coronary Endothelial Cells

Cited by 17 publications

References 30 publications

Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension

Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension

Parathyroid Hormone-Related Peptide Is Induced by Stimulation of α_1A-Adrenoceptors and Improves Resistance against Apoptosis in Coronary Endothelial Cells

Intrakrine, parakrine und autokrine Funktionen des PTH/PTHrP-Systems

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TGF- β1Downregulates PTHrP in Coronary Endothelial Cells

Cited by 17 publications

References 30 publications

Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension

Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension

Parathyroid Hormone-Related Peptide Is Induced by Stimulation of α1A-Adrenoceptors and Improves Resistance against Apoptosis in Coronary Endothelial Cells

Intrakrine, parakrine und autokrine Funktionen des PTH/PTHrP-Systems

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Parathyroid Hormone-Related Peptide Is Induced by Stimulation of α_1A-Adrenoceptors and Improves Resistance against Apoptosis in Coronary Endothelial Cells