Expression, Release, and Biological Activity of Parathyroid Hormone–Related Peptide From Coronary Endothelial Cells

Schlüter, K.-D.; Katzer, Christian; Frischkopf, Karen; Wenzel, Sibylle; Taimor, Gerhild; Piper, Hans Michael

doi:10.1161/01.res.86.9.946

Cited by 50 publications

(48 citation statements)

References 17 publications

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“…In years to come, we anticipate an overwhelming flow of new data and novel concepts on cardiac function, emerging from these signaling pathways, and further exemplifying, expanding, and clarifying our conjecture of the indispensable role of cardiac endothelial-myocardial interactions. Notably, MyoCapE of both fetal and adult heart abundantly express and release biologically active parathyroid hormone-related peptide (PTHrP), the expression of which is significantly upregulated by increased blood flow rate or by hypoxia, independently of the NO pathway (504,505). PTHrP (but not PTH) exerts a positive inotropic, chronotropic, and lusitropic effect in adult ventricular cardiomyocytes, which do not themselves express the hormone.…”

Section: Role Of Peptide Growth Factorsmentioning

confidence: 99%

Cardiac Endothelial-Myocardial Signaling: Its Role in Cardiac Growth, Contractile Performance, and Rhythmicity

Brutsaert

2003

Physiological Reviews

613

544

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Experimental work during the past 15 years has demonstrated that endothelial cells in the heart play an obligatory role in regulating and maintaining cardiac function, in particular, at the endocardium and in the myocardial capillaries where endothelial cells directly interact with adjacent cardiomyocytes. The emerging field of targeted gene manipulation has led to the contention that cardiac endothelial-cardiomyocytal interaction is a prerequisite for normal cardiac development and growth. Some of the molecular mechanisms and cellular signals governing this interaction, such as neuregulin, vascular endothelial growth factor, and angiopoietin, continue to maintain phenotype and survival of cardiomyocytes in the adult heart. Cardiac endothelial cells, like vascular endothelial cells, also express and release a variety of auto- and paracrine agents, such as nitric oxide, endothelin, prostaglandin I2, and angiotensin II, which directly influence cardiac metabolism, growth, contractile performance, and rhythmicity of the adult heart. The synthesis, secretion, and, most importantly, the activities of these endothelium-derived substances in the heart are closely linked, interrelated, and interactive. It may therefore be simplistic to try and define their properties independently from one another. Moreover, in relation specifically to the endocardial endothelium, an active transendothelial physicochemical gradient for various ions, or blood-heart barrier, has been demonstrated. Linkage of this blood-heart barrier to the various other endothelium-mediated signaling pathways or to the putative vascular endothelium-derived hyperpolarizing factors remains to be determined. At the early stages of cardiac failure, all major cardiovascular risk factors may cause cardiac endothelial activation as an adaptive response often followed by cardiac endothelial dysfunction. Because of the interdependency of all endothelial signaling pathways, activation or disturbance of any will necessarily affect the others leading to a disturbance of their normal balance, leading to further progression of cardiac failure.

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Section: Role Of Peptide Growth Factorsmentioning

confidence: 99%

Cardiac Endothelial-Myocardial Signaling: Its Role in Cardiac Growth, Contractile Performance, and Rhythmicity

Brutsaert

2003

Physiological Reviews

613

544

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“…[1][2][3] AVP is released both systemically from the pituitary gland and locally from the myocardium. 2,4 In addition, PTHrp is released from the heart in response to increased wall stress or hypoxia, 5 and PTHrp mRNA has been detected in isolated cardiomyocytes. 3,6 PTH and PTHrp are devoid of direct effects on ventricular contraction at physiological concentrations in vivo.…”

mentioning

confidence: 99%

Gene Transfer of Heterologous G Protein–Coupled Receptors to Cardiomyocytes

Laugwitz

Weig

Moretti

et al. 2001

Circulation Research

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Abstract-In heart failure, reduced cardiac contractility is accompanied by blunted cAMP responses to ␤-adrenergic stimulation. Parathyroid hormone (PTH)-related peptide and arginine vasopressin are released from the myocardium in response to increased wall stress but do not stimulate contractility or adenylyl cyclase at physiological concentrations.To bypass the defective ␤-adrenergic signaling cascade, recombinant P1 PTH/PTH-related peptide receptors (rPTH1-Rs) and V 2 vasopressin receptors (rV 2 -Rs), which are normally not expressed in the myocardium and which are both strongly coupled to adenylyl cyclase, and recombinant ␤ 2 -adrenergic receptors (r␤ 2 -ARs) were overexpressed in cardiomyocytes by viral gene transfer. The capacity of endogenous hormones to increase contractility via the heterologous, recombinant receptors was compared. Whereas V 2 -Rs are uniquely coupled to Gs, PTH1-Rs and ␤ 2 -ARs are also coupled to other G proteins. Gene transfer of rPTH1-Rs or r␤ 2 -ARs to adult cardiomyocytes resulted in maximally increased basal contractility, which could not be further stimulated by adding receptor agonists. Agonists at rPTH1-Rs induced increased cAMP formation and phospholipase C activity. In contrast, healthy or failing rV 2 -Rexpressing cardiomyocytes showed unaltered basal contractility. Their contractility and cAMP formation increased only at agonist exposure, which did not activate phospholipase C. In summary, we found that gene transfer of PTH1-Rs to cardiomyocytes results in constitutive activity of the transgene, as does that of ␤ 2 -ARs. In the absence of receptor agonists, rPTH1-Rs and r␤ 2 -ARs increase basal contractility, coupling to 2 G proteins simultaneously. In contrast, rV 2 -Rs are uniquely coupled to Gs and are not constitutively active, retaining their property to be activated exclusively on agonist stimulation. Therefore, gene transfer of V 2 -Rs might be more suited to test the effects of cAMP-stimulating receptors in heart failure than that of PTH1-Rs or ␤ 2 -ARs. (Circ Res. 2001;88:688-695.)Key Words: gene transfer Ⅲ receptor Ⅲ heart failure C ongestive heart failure is characterized by an increased sympatho-adrenergic drive; a stimulation of the reninangiotensin-aldosterone system; and an augmented release of several peptide hormones, among them atrial natriuretic peptide, arginine vasopressin (AVP), and parathyroid hormone (PTH)-related peptide (PTHrp). 1-3 AVP is released both systemically from the pituitary gland and locally from the myocardium. 2,4 In addition, PTHrp is released from the heart in response to increased wall stress or hypoxia, 5 and PTHrp mRNA has been detected in isolated cardiomyocytes. 3,6 PTH and PTHrp are devoid of direct effects on ventricular contraction at physiological concentrations in vivo. 7 In the cardiomyocyte, PTH and PTHrp induce hypertrophy acting via an endogenously occurring, yet uncloned, myocardial PTH receptor subtype 8 and therefore contribute to further worsening of heart failure. At physiological concentrations, neither PTH nor PT...

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“…Supernatants from coronary endothelial cells and cell fractions were used as described previously (Schluter et al, 2000). Samples containing 60 g of protein were loaded onto 12.5% SDS-polyacrylamide gel electrophoresis and blotted onto membranes.…”

Section: Methodsmentioning

confidence: 99%

“…Samples containing 60 g of protein were loaded onto 12.5% SDS-polyacrylamide gel electrophoresis and blotted onto membranes. Blots were incubated first with an antibody directed against PTHrP (antibody GF08; Calbiochem, Bad Soden, Germany) and then with an anti-mouse Ig antibody coupled to alkaline phosphatase (Schluter et al, 2000). The specificity of the antibody was proofed by blocking the antigen with synthetic PTHrP(1-84).…”

Section: Methodsmentioning

confidence: 99%

“…Unlike PTH, PTHrP is widely expressed throughout the body, including the vascular system. Within the vascular system, PTHrP is expressed in smooth muscle and endothelial cells (Thiede et al, 1990;Hongo et al, 1991;Ishikawa et al, 1994;Rian et al, 1994;Schluter et al, 2000). Smooth muscle cells, but not endothelial cells, also express a corresponding PTHrP receptor (Mok et al, 1989).…”

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confidence: 99%

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

Schorr

Taimor

Degenhardt

et al. 2003

Molecular Pharmacology

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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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Expression, Release, and Biological Activity of Parathyroid Hormone–Related Peptide From Coronary Endothelial Cells

Cited by 50 publications

References 17 publications

Cardiac Endothelial-Myocardial Signaling: Its Role in Cardiac Growth, Contractile Performance, and Rhythmicity

Cardiac Endothelial-Myocardial Signaling: Its Role in Cardiac Growth, Contractile Performance, and Rhythmicity

Gene Transfer of Heterologous G Protein–Coupled Receptors to Cardiomyocytes

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

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