PERK inhibition attenuates vascular remodeling in pulmonary arterial hypertension caused by BMPR2 mutation - Science
PERK inhibition attenuates vascular remodeling in pulmonary arterial hypertension caused by BMPR2 mutation - Science |
- PERK inhibition attenuates vascular remodeling in pulmonary arterial hypertension caused by BMPR2 mutation - Science
- New Hope Against Diseases Marked by Progressive Scarring of Lung Tissue - HealthDay News
- Tracleer for Digital Ulcers Lowers PH Risk in Scleroderma, Study Finds - Scleroderma News
- Prevalence, Incidence of PAH in SSc Steady Over Time, Report Says - AJMC.com Managed Markets Network
| Posted: 26 Jan 2021 11:14 AM PST  Not a PERK for pulmonary arterial hypertensionThe vascular remodeling that occurs in pulmonary arterial hypertension (PAH) is eventually fatal because it leads to right ventricular heart failure. PAH induces the unfolded protein response (UPR), and Shimizu et al. focused on the role of the UPR kinase PERK in PAH pathology. Genetic ablation or pharmacological inhibition of PERK limited vascular remodeling in two different mouse models of PAH and prevented mice from developing right ventricular heart failure. These effects involved suppressing the activation of PDGFRβ-STAT1 signaling and glycolysis in pulmonary artery smooth muscle cells. Thus, targeting PERK may help limit the mortality associated with PAH. AbstractPulmonary arterial hypertension (PAH) is a fatal disease characterized by excessive pulmonary vascular remodeling. However, despite advances in therapeutic strategies, patients with PAH bearing mutations in the bone morphogenetic protein receptor type 2 (BMPR2)–encoding gene present severe phenotypes and outcomes. We sought to investigate the effect of PER-like kinase (PERK), which participates in one of three major pathways associated with the unfolded protein response (UPR), on PAH pathophysiology in BMPR2 heterozygous mice. BMPR2 heterozygosity in pulmonary artery smooth muscle cells (PASMCs) decreased the abundance of the antiapoptotic microRNA miR124-3p through the arm of the UPR mediated by PERK. Hypoxia promoted the accumulation of unfolded proteins in BMPR2 heterozygous PASMCs, resulting in increased PERK signaling, cell viability, cellular proliferation, and glycolysis. Proteomic analyses revealed that PERK ablation suppressed PDGFRβ-STAT1 signaling and glycolysis in hypoxic BMPR2 heterozygous PASMCs. Furthermore, PERK ablation or PERK inhibition ameliorated pulmonary vascular remodeling in the Sugen/chronic hypoxia model of PAH, irrespective of BMPR2 status. Hence, these findings suggest that PERK inhibition is a promising therapeutic strategy for patients with PAH with or without BMPR2 mutation.  |
| New Hope Against Diseases Marked by Progressive Scarring of Lung Tissue - HealthDay News Posted: 15 Jan 2021 12:00 AM PST [unable to retrieve full-text content]New Hope Against Diseases Marked by Progressive Scarring of Lung Tissue HealthDay News  |
| Tracleer for Digital Ulcers Lowers PH Risk in Scleroderma, Study Finds - Scleroderma News Posted: 05 Jan 2021 12:00 AM PST People with scleroderma who were treated with Tracleer (bosentan) to prevent digital ulcers — open sores on the fingers or toes — saw their risk of developing pulmonary hypertension (PH) lowered almost four times, a study found. The study, "Effect of bosentan in pulmonary hypertension development in systemic sclerosis patients with digital ulcers," was published in the journal PLOS One. In scleroderma, poor blood flow and narrowed blood vessels can lead to ulcer formation (digital ulcers) on the toes and fingers, and particularly on the fingertips. It also causes the thickening of the connective tissue around the arteries of the lungs, which may result in pulmonary arterial hypertension or PAH — the most frequent cause of PH in scleroderma. Although several studies have investigated an association between digital ulcers and PAH, the results have been mixed, with some studies showing a link while others did not. Tracleer, a therapy developed by Actelion Pharmaceuticals (now part of Janssen), is approved in Europe to treat digital ulcers in both people with scleroderma and those with PAH. It works by stopping the action of endothelin, which is a molecule that causes blood vessels to narrow. However, whether patients treated with Tracleer for digital ulcers also have a lower risk of PAH is unclear. To find out, researchers at the Hospital Universitari de la Santa Creu i Sant Pau, in Spain, in collaboration with colleagues at the neighboring Hospital Universitari de Vall Hebron, analyzed the medical records of 222 people with SSc with a previous history of digital ulcers. A total of 59 patients (26.6%) had been treated with Tracleer for digital ulcers for at least one month, while 163 not given the medication were included as a control group. Of those selected, 201 (91%) were women, with a mean age of 63.9, including 138 patients with limited cutaneous scleroderma. An estimated pulmonary arterial pressure (mPAP) of more than 40 mmHg was observed in 21% of patients, thereby meeting the criterion for PH risk. For those given Tracleer, the median treatment length was 34 months, with the most common dose of 250 mg given twice daily to 60% of the participants. Tracleer is given as a tablet. Adverse events were reported in 35.6% of patients, including elevated liver enzymes and swelling; 27.1% of participants discontinued treatment. Most patients also were receiving other medications, known as vasodilators, to relax and widen blood vessels. During follow-up, 13.8% of patients treated with Tracleer and 23.7% of those without treatment developed PH, as estimated by echocardiogram, although this difference did not reach statistical significance. No major differences in blood flow parameters between treated and non-treated participants were observed. A statistical analysis found that participants without a history of Tracleer treatment had a 3.9 times higher risk of developing PH compared with treated patients. The risk in those who did not take a class of vasodilators called PDE5 inhibitors was 3.74 times higher. In patients who had never received vasodilators known as prostanoids, the risk was 2.65 times greater. No differences in risk were found among other concurrent treatments. After follow-up in the Tracleer group, lung function was stabilized without further decline (61.8% vs. 57% at study start) as measured by percentage carbon monoxide diffusing capacity (%DLCO) — a value to assess the lungs' ability to transfer oxygen to the blood. In contrast, the control group had significantly lower %DLCO values by the end of follow-up (65.5% vs. 60.5%). "In summary, our study demonstrates that patients who initiated bosentan [Tracleer] to prevent [digital ulcers] have a lower risk to present PH estimated by echocardiography and stabilizes DLCO," the researchers wrote. "A randomized control trial is warranted to demonstrate a protective effect of these specific drugs."  Steve holds a PhD in Biochemistry from the Faculty of Medicine at the University of Toronto, Canada. He worked as a medical scientist for 18 years, within both industry and academia, where his research focused on the discovery of new medicines to treat inflammatory disorders and infectious diseases. Steve recently stepped away from the lab and into science communications, where he's helping make medical science information more accessible for everyone. × Steve holds a PhD in Biochemistry from the Faculty of Medicine at the University of Toronto, Canada. He worked as a medical scientist for 18 years, within both industry and academia, where his research focused on the discovery of new medicines to treat inflammatory disorders and infectious diseases. Steve recently stepped away from the lab and into science communications, where he's helping make medical science information more accessible for everyone. Latest Posts  |
| Prevalence, Incidence of PAH in SSc Steady Over Time, Report Says - AJMC.com Managed Markets Network Posted: 29 Jan 2021 12:34 PM PST  In this study, the authors said they applied newer recommendations for diagnosing PAH, and as a result, they said their results show the "largest and most accurate metanalysis focused on the prevalence and incidence of SSc-related PAH. The study, published in Autoimmunity Reviews, examined databases from June 1962 to May 2019. The researchers wrote that the criteria for a PAH diagnosis were mean pulmonary arterial pressure >25 mm Hg plus pulmonary capillary wedge pressure <15 mm Hg. When available and reported in previous studies, they also included data on pulmonary vascular resistance >3 WU, which is now part of the current definition of PAH. The first pass found 2115 articles; of those, 1972 articles were not included. Of the 143 articles selected for full-text review, 24 were eventually selected for the global prevalence meta-analysis and 15 were selected for the incidence meta-analysis. The global prevalence review contained data on 9804 patients with SSc. The overall PAH prevalence was determined to be 6.4% (95% CI, 5%-8.3%). The study also examined the prevalence of PAH in limited cutaneous systemic sclerosis (lcSSc), with 14 studies containing data on 4987 patients. The PAH prevalence found in lcSSc was 7.7% (95% CI, 5.3%-11.1%). Twelve studies were included in the PAH prevalence study for diffuse cutaneous systemic sclerosis (dcSSc), with data on 1790 dcSSc patients. The PAH prevalence found in dcSSc was 6.3% (95% CI, 4.5%-8.9%). Fifteen studies, involving data from 5926 patients with SSc, looked at the PAH incidence of an entire SSc cohort. The overall PAH incidence was 18.2 cases per 1000 person-years (95% CI, 12-27.4). Looking again only at lcSSc, 8 studies with data on 2721 patients were reviewed for PAH incidence, which was determined to be 20.4 cases per 1000 person-years (95% CI, 10.1-41.1). And 7 studies, with 942 patients with dcSSc, were analyzed for PAH incidence, showing an overall PAH incidence in dcSSc of 16.6 cases per 1000 person-years (95% CI, 8.5-32.1). Overall prevalence and incidence in PAH was stable over time, the researchers reported, but they also found a trend towards declining PAH prevalence and incidence in patients with lcSSc and increasing PAH prevalence and incidence rate in dcSSc. Reference Rubio-Rivas M, Homs NA, Cuartero D, Corbella X. The prevalence and incidence rate of pulmonary arterial hypertension in systemic sclerosis: systematic review and meta-analysis. Autoimmun Rev. 2021;20(1):102713. doi:10.1016/j.autrev.2020.102713  |
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