Parathyroid Hormone-Related Peptide Is Induced by Stimulation of α<sub>1A</sub>-Adrenoceptors and Improves Resistance against Apoptosis in Coronary Endothelial Cells

Schorr, Katja; Taimor, Gerhild; Degenhardt, Heike; Weber, Kerstin; Schlüter, Klaus‐Dieter

doi:10.1124/mol.63.1.111

Cited by 18 publications

(22 citation statements)

References 31 publications

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“…These effects were elicited by exogenous peptides and are paracrine in nature. In many cases, PTHrP elicits effects on apoptosis after localization to the nucleus (14,29,32), actions that are termed "intracrine" effects. We have not investigated the intracrine effects of PTHrP in lung cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…PTHrP might contribute to cancer progression by stimulating cancer cell growth and/or inhibiting apoptosis. PTHrP-(1-34) is a growth stimulant in many malignant cell lines, including human lung cancer cells (4,19), and it inhibits apoptosis in various cells, including growth plate chondrocytes, pancreatic ␤-cells, LNCaP prostate carcinoma cells, MCF-7 breast carcinoma cells, cerebellar neurons, cytotrophoblasts, and coronary endothelial cells (5,8,14,26,29). The effects of PTHrP on lung cancer cell apoptosis are unknown.…”

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confidence: 99%

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Parathyroid hormone-related protein ameliorates death receptor-mediated apoptosis in lung cancer cells

Hastings¹,

Araiza²,

Burton³

et al. 2003

American Journal of Physiology-Cell Physiology

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Parathyroid hormone-related protein (PTHrP) is expressed in more advanced, aggressive tumors and may play an active role in cancer progression. This study investigated the effects of PTHrP on apoptosis after UV irradiation, Fas ligation, or staurosporine treatment in BEN human squamous lung carcinoma cells. Cells at 70% confluency were treated for 24 h with 100 nM PTHrP-(1-34), PTHrP-(38-64), PTHrP-(67-86), PTHrP-(107-139), or PTHrP-(140-173) in media with serum, exposed for 30 min to UV-B radiation (0.9 mJ/cm2), and maintained for another 24 h. Caspase-3, caspase-8, and caspase-9 activities increased fivefold. Pretreatment with PTHrP-(1-34) and PTHrP-(140-173) ameliorated apoptosis after UV irradiation, as indicated by reduced caspase activities, increased cell protein, decreased nuclear condensation, and increased clonal survival. Other peptides had no effect on measures of apoptosis. PTHrP-(140-173) also reduced caspase activities after Fas ligation by activating antibody, but neither peptide had effects on caspase-3 or caspase-9 activity after 1 μM staurosporine. These data indicate that PTHrP-(1-34) and PTHrP-(140-173) protect against death receptor-induced apoptosis in BEN lung cancer cells but are ineffective against mitochondrial pathways. PTHrP contributes to lung cancer cell survival in culture and could promote cancer progression in vivo. The mechanism for the protective effect against apoptosis remains to be determined.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Parathyroid hormone-related protein ameliorates death receptor-mediated apoptosis in lung cancer cells

Hastings¹,

Araiza²,

Burton³

et al. 2003

American Journal of Physiology-Cell Physiology

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“…The antiapoptotic properties of PTHrP have been observed in a variety of cell types (20,(31)(32)(33)(34)(35)(36)(37). While the molecular mechanisms by which PTHrP signaling in the osteoblast prevents apoptotic cell death remain to be determined, a number of them may be operative.…”

Section: Discussionmentioning

confidence: 99%

“…While the molecular mechanisms by which PTHrP signaling in the osteoblast prevents apoptotic cell death remain to be determined, a number of them may be operative. These include paracrine/autocrine actions involving upregulation of Bcl2 expression (32) as well as intracrine mechanisms (31,34,35) via modulation of ribosome synthesis (38), or interaction of the internalized receptor with 14-3-3 proteins (39), a family of phosphoserine/phosphothreonine-binding molecules suggested to support cell survival.…”

Section: Discussionmentioning

confidence: 99%

Osteoblast-derived PTHrP is a potent endogenous bone anabolic agent that modifies the therapeutic efficacy of administered PTH 1-34

Miao

He²,

Jiang³

et al. 2005

Journal of Clinical Investigation

255

192

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Mice heterozygous for targeted disruption of Pthrp exhibit, by 3 months of age, diminished bone volume and skeletal microarchitectural changes indicative of advanced osteoporosis. Impaired bone formation arising from decreased BM precursor cell recruitment and increased apoptotic death of osteoblastic cells was identified as the underlying mechanism for low bone mass. The osteoporotic phenotype was recapitulated in mice with osteoblast-specific targeted disruption of Pthrp, generated using Cre-LoxP technology, and defective bone formation was reaffirmed as the underlying etiology. Daily administration of the 1-34 amino-terminal fragment of parathyroid hormone (PTH 1-34) to Pthrp +/-mice resulted in profound improvement in all parameters of skeletal microarchitecture, surpassing the improvement observed in treated WT littermates. These findings establish a pivotal role for osteoblast-derived PTH-related protein (PTHrP) as a potent endogenous bone anabolic factor that potentiates bone formation by altering osteoblast recruitment and survival and whose level of expression in the bone microenvironment influences the therapeutic efficacy of exogenous PTH 1-34.

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“…The effects of PTH on the functional derangements of cardiomyocytes both in vivo and in vitro [8] as well as on structural myocardial changes such as hypertrophy, fibrosis, and apoptosis in experimental renal failure have been previously described [8, 11, 20]. On the other hand, it is accepted that PTH has a pathophysiological role in several of the cardiovascular complications of uremic patients [9, 10].…”

Section: Discussionmentioning

confidence: 99%

Effect of Parathyroidectomy on Cardiac Fibrosis and Apoptosis: Possible Role of Aldosterone

Rodríguez-Ayala

Ávila-Díaz²,

Foyo-Niembro³

et al. 2006

Nephron Physiol

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Background/Aim: It has been demonstrated that parathyroidectomy prevents left ventricular hypertrophy in uremic animals. Although this effect may be mediated by direct actions of parathormone (PTH), it may also be exerted through regulation of profibrotic factors such as aldosterone. In adrenal cortex cell cultures, PTH increases aldosterone release. The objective of this work is to assess the effect of parathyroidectomy on aldosterone levels and on cardiac fibrosis and apoptosis in uremic rats. Methods: Four groups of rats were studied: C, control; 5/6Nx, 5/6 nephrectomy; PTx, parathyroidectomy, and 5/6NxPTx, 5/6 nephrectomy plus parathyroidectomy. Thirty days after the last surgical procedure the animals were sacrificed. Serum creatinine, ionized calcium, aldosterone, PTH, cardiac weight, fibrosis and apoptosis were measured. Results: Serum creatinine levels were significantly higher in 5/6Nx and 5/6NxPTx groups (1.62 ± 0.21 and 1.38 ± 0.15 mg/dl) than in C and PTx groups (0.66 ± 0.02 and 0.47 ± 0.01 mg/dl, p < 0.001). Potassium levels were significantly higher in the 5/6Nx and 5/6NxPTx groups (5.2 ± 0.3 and 5.4 ± 0.3 mg/dl) than in the C group (4.3 ± 0.06 mg/dl, p < 0.05). Values in 5/6Nx and 5/6NxPTx groups were not significantly different from each other. PTH levels were significantly higher in the 5/6Nx group (470.5 ± 156.3 µg/ml) than in the controls (102.3 ± 14.3 µg/ml). PTH levels in the PTx group (1.78 ± 0.52 µg/ml) and in the 5/6NxPTx group (81.64 ± 32.15 µg/ml) were similar to control values. Ionized calcium was lower in PTx and 5/6NxPTx groups (0.80 ± 0.07 and 0.89 ± 0.07 mmol/l) as compared with C and 5/6Nx groups (1.14 ± 0.01 and 0.96 ± 0.01 mmol/ l, p < 0.01). The heart weight as percentage of the body weight increased significantly in 5/6Nx animals (4.20 ± 0.15%) compared to the C group (3.41 ± 0.27%, p < 0.05); parathyroidectomy reversed the heart weight increment in the 5/6NxPTx animals (3.58 ± 0.16%). Myocardial fibrosis was significantly higher in the 5/6Nx group (12.5 ± 1.1%) than in the C group (7.3 ± 1.5%, p < 0.001); in the 5/6NxPTx animals fibrosis returned towards control values (8.9 ± 0.2%). Myocardial apoptosis rose significantly in 5/6Nx animals (24.3 ± 1.2%) compared to the C group (6.7 ± 0.83%, p < 0.001); parathyroidectomy reversed the apoptosis in the 5/6NxPTx animals (10.4 ± 0.49%). Aldosterone levels increased significantly in the 5/6Nx group (2,461 ± 257 pg/ml) compared to the C group (703 ± 81 pg/ml, p < 0.001); in the 5/6NxPTx animals aldosterone levels were below control values (509 ± 99 pg/ml). Conclusions: Uremia was associated to myocardial hypertrophy, fibrosis and apoptosis. Surgically induced hypoparathyroidism prevented the development of these disorders. Our results suggest that in the remnant kidney rat model myocardial hypertrophy, fibrosis, and apoptosis are mediated by high circulating aldosterone levels. Aldosterone, in turn, may be regulated by PTH.

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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

Cited by 18 publications

References 31 publications

Parathyroid hormone-related protein ameliorates death receptor-mediated apoptosis in lung cancer cells

Parathyroid hormone-related protein ameliorates death receptor-mediated apoptosis in lung cancer cells

Osteoblast-derived PTHrP is a potent endogenous bone anabolic agent that modifies the therapeutic efficacy of administered PTH 1-34

Effect of Parathyroidectomy on Cardiac Fibrosis and Apoptosis: Possible Role of Aldosterone

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

Cited by 18 publications

References 31 publications

Parathyroid hormone-related protein ameliorates death receptor-mediated apoptosis in lung cancer cells

Parathyroid hormone-related protein ameliorates death receptor-mediated apoptosis in lung cancer cells

Osteoblast-derived PTHrP is a potent endogenous bone anabolic agent that modifies the therapeutic efficacy of administered PTH 1-34

Effect of Parathyroidectomy on Cardiac Fibrosis and Apoptosis: Possible Role of Aldosterone

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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