Effect of nitric oxide deficiency on the pulmonary <scp>PTH</scp>rP system

Brockhoff, Bastian; Schreckenberg, Rolf; Forst, Svenja; Heger, Jacqueline; Bencsik, Péter; Kiss, Krisztina; Ferdinándy, Péter; Schulz, Rainer; Schlüter, K.-D.

doi:10.1111/jcmm.12942

Cited by 2 publications

(3 citation statements)

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“…[1][2][3][4] Pulmonary vasoconstriction is induced by the reduction of vasodilators such as nitric oxide (NO) and/or the production of vasoconstrictors such as endothelin-1 and oxidative stress. [5][6][7][8] In addition, it is known that resistance to apoptosis mediated by bone morphogenic protein (BMP) signals or transforming growth factor (TGF)-β signals is involved in the excessive proliferation of pulmonary artery endothelial cells and smooth muscle cells. [9][10][11] However, the detailed mechanisms remain unclear.…”

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confidence: 99%

Senescence Marker Protein 30 Deficiency Exacerbates Pulmonary Hypertension in Hypoxia-Exposed Mice

et al. 2019

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Pulmonary arterial hypertension is a fatal disease caused by pulmonary arterial vasoconstriction and organic stenosis due to the proliferation of pulmonary smooth muscle cells and endothelial cells. Endothelial dysfunction, including impaired nitric oxide (NO) bioavailability, plays a crucial role in the pathogenesis of pulmonary hypertension, and endothelial nitric oxide synthase (eNOS) is an important modulator of pulmonary vasodilatation. Although senescence marker protein (SMP) 30 is known as an anti-aging protein, the role of SMP30 in pulmonary vessels is still unclear. In this study, we examined the role of SMP30 in pulmonary vasculature using SMP30-deficient mice. We used female SMP30-deficient mice and wild-type littermate (WT) mice at the age of 12 to 18 weeks. The WT and SMP30-deficient mice were exposed to normoxia or hypoxia (10% oxygen for 4 weeks). In normoxia, the right ventricular systolic pressure (RVSP) was not different between the WT and SMP30-deficient mice, but in hypoxia, the RVSP was significantly higher in the SMP30-deficient mice compared to the WT mice (P < 0.05). The hypoxia-induced increases in right ventricular hypertrophy and medial smooth muscle area of the pulmonary artery were comparable between the WT and the SMP30-deficient mice. Western blotting showed that eNOS phosphorylation in lung tissue was reduced in the SMP30-deficient mice compared to the WT mice in normoxia. However, in hypoxic conditions, eNOS phosphorylation was reduced in both the WT and SMP30-deficient mice with no differences in Akt phosphorylation. Our study demonstrated that SMP30 is involved in the development of hypoxia-induced pulmonary hypertension by impairment of eNOS activity.

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confidence: 99%

Senescence Marker Protein 30 Deficiency Exacerbates Pulmonary Hypertension in Hypoxia-Exposed Mice

et al. 2019

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“…Former studies showed that lung structural remodelling after myocardial infarction can be attenuated by irbesartan, an angiotensin II receptor antagonist [12]. We have recently shown that captopril, an angiotensin converting enzyme inhibitor, can attenuate pulmonary induction of PTHrP, but not that of PTH-1 receptor, in a NO-deficiency model [1]. Collectively the data suggest that an infarct-dependent activation of the renin-angiotensin-system induces the expression of PTHrP and that this contributes to the formerly observed lung structural remodelling.…”

Section: Discussionmentioning

confidence: 98%

“…Our finding that elastin mRNA expression was not changed under conditions shown to increase pulmonary PTHrP mRNA expression is in fine agreement with the assumption that activation of the pulmonary PTHrP system attenuates transactivation of epithelial cells to myofibroblasts that favours pulmonary fibrosis. We have recently shown that the pulmonary expression of PTHrP is constitutively repressed by nitric oxide (NO) [1]. Inhibition of endothelial-derived NO formation significantly increased the expression of PTHrP, PTH-1 receptor, ADRP, and PPARγ.…”

Section: Discussionmentioning

confidence: 99%

Effect of high fat diet on pulmonary expression of parathyroid hormone-related protein and its downstream targets

Oruqaj¹,

Forst²,

Schreckenberg³

et al. 2016

Heliyon

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AimsParathyroid hormone-related protein (PTHrP) is involved in lung development and surfactant production. The latter one requires a paracrine interaction between type II alveolar cells and lipofibroblasts in which leptin triggers PTHrP-induced effects. Whether increased plasma leptin levels, as they occur in high fat diet, modify the expression of PTHrP remains unclear. Furthermore, the effect of high fat diet under conditions of forced pulmonary remodelling such as response to post myocardial infarction remains to be defined.Materials and methodsC57 bl/6 mice were randomized to either normal diet or high fat diet at an age of 6 weeks. Seven months later, the mice were euthanized and the lung was removed and frozen in fluid nitrogen until use. Samples were analyzed by real-time RT-PCR and western blot. Leptin deficient mice were used to investigate the effect of leptin on pulmonary expression of PTHrP more directly. A subgroup of mice with and without high fat diet underwent in vivo ischemia (45 min) and reperfusion (4 weeks). Finally, experiments were repeated with prolonged high-fat diet.Key findingsHigh fat diet increased plasma leptin levels by 30.4% and the pulmonary mRNA expression of PTHrP (1,447-fold), PTH-1 receptor (4.21-fold), and PTHrP-downstream targets ADRP (7.54-fold) and PPARγ (5.27-fold). Pulmonary PTHrP expression was reduced in leptin deficient mice by 88% indicating leptin dependent regulation. High fat diet further improved changes in pulmonary adaptation caused by ischemia/reperfusion (1.48-fold increased PTH-1 receptor protein expression). These effects were lost during prolonged high fat diet.SignificanceThis study established that physiological regulation of leptin plasma levels by high fat diet affects the pulmonary PTHrP expression and of PTHrP downstream targets. Modification of pulmonary expression of PTH-1 receptors by high fat diet after myocardial infarction suggests that the identified interaction may participate in the obesity paradox.

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Effect of nitric oxide deficiency on the pulmonary PTHrP system

Cited by 2 publications

References 37 publications

Senescence Marker Protein 30 Deficiency Exacerbates Pulmonary Hypertension in Hypoxia-Exposed Mice

Senescence Marker Protein 30 Deficiency Exacerbates Pulmonary Hypertension in Hypoxia-Exposed Mice

Effect of high fat diet on pulmonary expression of parathyroid hormone-related protein and its downstream targets

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