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Published on: September 26, 2018
Cilostazol Attenuates AngII-Induced Cardiac Fibrosis in apoE Deficient Mice
Yoshiko Hada1, Haruhito A Uchida1,2, Ryoko Umebayashi1
1Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
Insights
Cilostazol, a drug for peripheral artery disease, was found to protect against Angiotensin II-induced cardiac fibrosis in mice. This protective effect involves the activation of the cAMP-PKA pathway, reducing fibrotic and inflammatory markers.
Area of Science:
- Cardiology
- Pharmacology
- Molecular Biology
Background:
- Cardiac fibrosis, characterized by extracellular matrix accumulation, is a key feature of heart disease.
- Cilostazol, a phosphodiesterase type III inhibitor, has anti-platelet and vasodilating effects.
- Angiotensin II (AngII) is implicated in promoting cardiac fibrosis.
Purpose of the Study:
- To investigate the potential protective effects of cilostazol against Angiotensin II-induced cardiac fibrosis.
- To elucidate the molecular mechanisms underlying cilostazol's action in the context of cardiac fibrosis.
Main Methods:
- Male apolipoprotein E-deficient mice were treated with cilostazol and infused with AngII or saline.
- Cardiac fibrosis, heart/body weight ratio, and gene/protein expression (fibrotic, inflammatory, osteopontin) were assessed.
- In vitro studies using cultured human cardiac myocytes examined cilostazol's effect on AngII-induced osteopontin expression via the cAMP-PKA pathway.
Main Results:
- AngII infusion significantly increased heart/body weight ratio and cardiac fibrosis, which were attenuated by cilostazol.
- Cilostazol significantly reduced AngII-induced increases in fibrotic and inflammatory gene expression.
- Cilostazol inhibited AngII-induced osteopontin expression in vivo and in vitro, mediated by cAMP-PKA pathway activation.
Conclusions:
- Cilostazol exhibits a protective effect against Angiotensin II-induced cardiac fibrosis in mice.
- The cardioprotective mechanism of cilostazol involves the activation of the cAMP-PKA pathway.
- Cilostazol may represent a therapeutic strategy for managing cardiac fibrosis.
Abstract:
Cardiac fibrosis is characterized by the net accumulation of extracellular matrix in the myocardium and is an integral component of most pathological cardiac conditions. Cilostazol, a selective inhibitor of phosphodiesterase type III with anti-platelet, anti-mitogenic, and vasodilating properties, is widely used to treat the ischemic symptoms of peripheral vascular disease. Here, we investigated whether cilostazol has a protective effect against Angiotensin II (AngII)-induced cardiac fibrosis. Male apolipoprotein E-deficient mice were fed either a normal diet or a diet containing cilostazol (0.1% wt/wt). After 1 week of diet consumption, the mice were infused with saline or AngII (1000 ng kg−1 min−1) for 28 days. AngII infusion increased heart/body weight ratio (p < 0.05), perivascular fibrosis (p < 0.05), and interstitial cardiac fibrosis (p < 0.0001), but were significantly attenuated by cilostazol treatment (p < 0.05, respectively). Cilostazol also reduced AngII-induced increases in fibrotic and inflammatory gene expression (p < 0.05, respectively). Furthermore, cilostazol attenuated both protein and mRNA abundance of osteopontin induced by AngII in vivo. In cultured human cardiac myocytes, cilostazol reduced mRNA expression of AngII-induced osteopontin in dose-dependent manner. This reduction was mimicked by forskolin treatment but was cancelled by co-treatment of H-89. Cilostazol attenuates AngII-induced cardiac fibrosis in mice through activation of the cAMP−PKA pathway.
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