Differential Regulatory Role of Soluble Klothos on Cardiac Fibrogenesis in Hypertension
| Autor: | Yuanjian Chen, Gwendalyn D. King, Yao Sun, Xue Liu, Syamal K. Bhattacharya, Cody W. McCoy, Min Pi, Tieqiang Zhao, Darryl L. Quarles |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Pathology medicine.medical_specialty Cardiac fibrosis Primary Cell Culture urologic and male genital diseases Fibroblast growth factor Collagen Type I 03 medical and health sciences Downregulation and upregulation Fibrosis Internal medicine Internal Medicine medicine Animals Protein Isoforms Extracellular Signal-Regulated MAP Kinases Myofibroblasts Klotho Klotho Proteins Glucuronidase business.industry Wild type Cell Differentiation medicine.disease female genital diseases and pregnancy complications Fibroblast Growth Factors Mice Inbred C57BL 030104 developmental biology Endocrinology Hypertension Phosphorylation Original Article business Cardiomyopathies Myofibroblast |
| Zdroj: | American journal of hypertension. 29(10) |
| ISSN: | 1941-7225 |
| Popis: | BACKGROUND Soluble Klotho functions as an endocrine factor that plays important roles in a variety of pathophysiological processes. Soluble Klotho contains 130 KDa and 65 KDa isoforms. However, their distinct individual functional heterogeneity remains uncertain. Herein, we investigated the regulatory role of two soluble Klothos on cardiac fibrogenic responses. METHODS AND RESULTS The effect of soluble Klothos on myofibroblast differentiation, proliferation, and collagen synthesis/degradation were examined in cultured mouse cardiac myofibroblasts. The role of 130 KDa Klotho on fibrosis in hypertensive heart disease were examined in wild type (WT) and Klotho transgenic (Tg/+) mice receiving chronic angiotensin (Ang)II infusion. Our in vitro studies revealed that addition of 130 KDa soluble Klotho isoform increased collagen synthesis in a dose dependent manner. Furthermore, 130 KDa Klotho significantly stimulated myofibroblast differentiation, proliferation, and ERK phosphorylation, which were abolished by fibroblast growth factor (FGF) receptor antagonist (SU5402). In contrast, 65 KDa soluble Klotho treatment significantly suppressed myofibroblast proliferation and collagen synthesis. In vivo study further demonstrated that chronic AngII infusion lead to cardiac fibrosis in both WT and Tg/+ mice. However, cardiac collagen, TGF-β1, TIMP-2, and α-smooth muscle actin (SMA) levels were markedly upregulated in Tg/+ mice compared to WT cohort. CONCLUSION Taken together, these findings implicate that 130 KDa soluble Klotho plays a stimulatory role in cardiac myofibroblast growth and activity through FGF pathway, whereas 65 KDa soluble Klotho exerts an anti-fibrotic effect in cardiac myofibroblasts. Thus, two distinct isoforms of soluble Klotho appear to play the counter-regulatory roles in cardiac fibrogenic responses. |
| Databáze: | OpenAIRE |
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