A novel ACE2 activator reduces monocrotaline-induced pulmonary hypertension by suppressing the JAK/STAT and TGF-β cascades with restored caveolin-1 expression
| Autor: | Shiori Haga, Yukihito Ishizaka, Takaichi Hamano, Akio Mimori, Hirai Toshitake, Haruka Tsuchiya |
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| Rok vydání: | 2014 |
| Předmět: |
Pulmonary and Respiratory Medicine
Male medicine.medical_specialty Heart Ventricles Hypertension Pulmonary Clinical Biochemistry Caveolin 1 Drug Evaluation Preclinical Peptidyl-Dipeptidase A Rats Sprague-Dawley Right ventricular hypertrophy Transforming Growth Factor beta Internal medicine medicine.artery Renin–angiotensin system medicine Animals Molecular Biology Oxazoles Janus Kinases Feedback Physiological Lung Monocrotaline Hypertrophy Right Ventricular Activator (genetics) business.industry medicine.disease Pulmonary hypertension Enzyme Activation STAT Transcription Factors Endocrinology medicine.anatomical_structure Pyrimidines Pulmonary artery Ventricular pressure Angiotensin-Converting Enzyme 2 business hormones hormone substitutes and hormone antagonists |
| Zdroj: | Experimental lung research. 41(1) |
| ISSN: | 1521-0499 |
| Popis: | Pulmonary hypertension (PH) is characterized by increased pressure in the pulmonary artery and right ventricular hypertrophy (RVH). Recently, angiotensin-converting enzyme 2 (ACE2), which converts angiotensin (Ang) II into Ang-(1-7), was shown to inhibit experimental PH. Here we identified a novel ACE2 activator and investigated how the compound reduced monocrotaline (MCT)-induced PH.To induce PH, Sprague-Dawley rats were injected subcutaneously with MCT, followed by the continuous administration of NCP-2454, an ACE2 activator, using osmotic pumps. Pulmonary arterial compliance was monitored every week until 4 weeks post-injection (wpi). RVH and lung remodeling was evaluated using lung tissue at 4 wpi.NCP-2454 upregulated the production of Ang-(1-7) when incubated with ACE2 and Ang II. Notably, a continuous infusion of NCP-2454 significantly improved pulmonary arterial compliance, right ventricular systolic pressure, and RVH in MCT-treated rats. Interestingly, NCP-2454 increased the relative expression of ACE2 and MAS mRNA in lung tissue, especially in MCT-treated rats. In addition, the compound inhibited the MCT-induced overexpression of transforming growth factor β, phosphorylation of signal transducer and activator of transcription-3 (STAT3), and interleukin-6 production. The compound also restored the expression of caveolin-1 (Cav-1), which negatively regulates the Janus kinase-STAT signaling cascade.NCP-2454 prevented MCT-induced PH by suppressing intracellular inflammatory cascades, an upstream molecular change of which is the disruption of Cav-1 expression. |
| Databáze: | OpenAIRE |
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