Monocrotaline-Induced Pulmonary Hypertension Involves Downregulation of Antiaging Protein Klotho and eNOS Activity

Varshney, Rohan; Ali, Quaisar; Wu, Chih Yang; Sun, Zhongjie

doi:10.1161/hypertensionaha.116.08184

Cited by 42 publications

(27 citation statements)

References 54 publications

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“…Recently, it has been reported that the reduction of Klotho protein, which is an anti-aging protein, is involved in the reduction of NOS of the pulmonary artery in monocrotaline-induced pulmonary hypertension rats. 36) These results, including ours, suggest that anti-aging proteins regulate eNOS bioavailability, and affect the pathogenesis of pulmonary hypertension.…”

Section: Discussionsupporting

confidence: 53%

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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Section: Discussionsupporting

confidence: 53%

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

et al. 2019

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“…The histological and IHC analysis was performed as described in our recent studies (Chen, Lin & Sun, 2016; Gao et al., 2016; Lin, Chen & Sun, 2016; Lin & Sun, 2015a,b; Varshney, Ali, Wu & Sun, 2016). For details, see Data S1.…”

Section: Methodsmentioning

confidence: 99%

Activation of DNA demethylases attenuates aging‐associated arterial stiffening and hypertension

Chen

Sun

2018

Aging Cell

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Summary DNA methylation increases with age. The objective of this study was to investigate whether compound H, a potential activator of DNA demethylases, attenuates aging‐related arterial stiffness and hypertension. Aged mice (24–27 months) and adult mice (12 months) were used. Pulse wave velocity (PWV), a direct measure of arterial stiffness, and blood pressure (BP) were increased significantly in aged mice. Notably, daily treatments with compound H (15 mg/kg, IP) for 2 weeks significantly attenuated the aging‐related increases in PWV and BP. Compound H abolished aging‐associated downregulation of secreted Klotho (SKL) levels in both kidneys and serum likely by enhancing DNA demethylase activity and decreasing DNA methylation. Aging‐related arterial stiffness was associated with accumulation of stiffer collagen and degradation of compliant elastin which are accompanied by increased expression of MMP2, MMP9, TGF‐β1, and TGF‐β3. These changes were effectively attenuated by compound H, suggesting rejuvenation of aged arteries. Compound H also rescued downregulation of Sirt1 deacetylase, AMPKα, and eNOS activities in aortas of aged mice. In cultured smooth muscle cells (SMCc) Klotho‐deficient serum upregulated expression of MMPs and TGFβ which, however, was not affected by compound H. In conclusion, compound H attenuates aging‐associated arterial stiffness and hypertension by activation of DNA demethylase which increases renal SKL expression and consequently circulating SKL levels leading to activation of the Sirt1‐AMPK‐eNOS pathway in aortas of aged mice.

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“…Furthermore, the authors demonstrated in the same experiment that the addition of soluble klotho without FGF23 to mouse aorta rings induced vasoconstriction and the production of ROS. The increase in endothelial NO following soluble klotho administration could explain the antagonistic effects of klotho to monocrotalineinduced experimental PAH in murine models (12). However, the evaluation of soluble a-klotho in the peripheral blood from 64 precapillary PAH patients did not find a significant association with haemodynamic findings (13).…”

Section: Original Papermentioning

confidence: 99%

The role of klotho in systemic sclerosis

Talotta¹,

Bongiovanni²,

Letizia³

et al. 2017

Reumatismo

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The aim was to evaluate the role of klotho in the pathogenesis of systemic sclerosis (SSc), through the measurement of its serum concentration in SSc patients compared to healthy controls, and to assess the association with cutaneous and visceral involvement. Blood samples obtained from both SSc patients and healthy controls were analysed by an ELISA assay for the detection of human klotho. SSc patients were globally evaluated for disease activity and assessed through the modified Rodnan’s Skin Score, Medsger’s scale, pulmonary function tests, 2D-echocardiography, nailfold capillaroscopy and laboratory tests. Our cohort consisted of 69 SSc patients (61 females, mean age 64.5±12.5 years, median disease duration 9.0 (IQR 8) years) and 77 healthy controls (28 females, mean age 49.7±10.2 years). In the group of SSc patients, 19 (27.5%) suffered from a diffuse form of SSc. All patients were receiving IV prostanoids, and some of them were concomitantly treated with immunosuppressive drugs (prednisone, hydroxychloroquine, mofetil mycophenolate, methotrexate, cyclosporin A and azathioprine). The median serum concentration of klotho was significantly lower in patients compared to controls (0.23 ng/mL vs 0.60 ng/mL; p<0.001). However, Spearman’s test showed no significant association between klotho serum levels and disease activity, concerning either clinical, laboratory or instrumental findings. Our data show a significant deficit of klotho in SSc patients although any significant association was detected between klotho serum concentration and the clinical, laboratory or instrumental features of the disease. However, due to the limits of the study, further investigations are required.

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Monocrotaline-Induced Pulmonary Hypertension Involves Downregulation of Antiaging Protein Klotho and eNOS Activity

Cited by 42 publications

References 54 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

Activation of DNA demethylases attenuates aging‐associated arterial stiffening and hypertension

The role of klotho in systemic sclerosis

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