Yuichiro Yamada1, Shino Takeuchi2, Mamoru Yoneda1, Shogo Ito1, Yusuke Sano1, Kai Nagasawa1, Natsumi Matsuura1, Ayako Uchinaka1, Toyoaki Murohara3, Kohzo Nagata4. 1. Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan. 2. Department of Medical Technology, Nagoya University School of Health Sciences, Nagoya, Japan. 3. Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan. 4. Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address: nagata@met.nagoya-u.ac.jp.
Abstract
BACKGROUND: Statins are strong inhibitors of cholesterol biosynthesis and help to prevent cardiovascular disease. They also exert additional pleiotropic effects that include an anti-inflammatory action and are independent of cholesterol, but the molecular mechanisms underlying these additional effects have remained unclear. We have now examined the effects of atorvastatin on cardiac and adipose tissue inflammation in DahlS.Z-Leprfa/Leprfa (DS/obese) rats, which we previously established as a model of metabolic syndrome (MetS). METHODS AND RESULTS: DS/obese rats were treated with atorvastatin (6 or 20mgkg-1day-1) from 9 to 13weeks of age. Atorvastatin ameliorated cardiac fibrosis, diastolic dysfunction, oxidative stress, and inflammation as well as adipose tissue inflammation in these animals at both doses. The high dose of atorvastatin reduced adipocyte hypertrophy to a greater extent than did the low dose. Atorvastatin inhibited the up-regulation of peroxisome proliferator-activated receptor γ gene expression in adipose tissue as well as decreased the serum adiponectin concentration in DS/obese rats. It also activated AMP-activated protein kinase (AMPK) as well as inactivated nuclear factor-κB (NF-κB) in the heart of these animals. The down-regulation of AMPK and NF-κB activities in adipose tissue of DS/obese rats was attenuated and further enhanced, respectively, by atorvastatin treatment. CONCLUSIONS: The present results suggest that the anti-inflammatory effects of atorvastatin on the heart and adipose tissue are attributable at least partly to increased AMPK activity and decreased NF-κB activity in this rat model of MetS.
BACKGROUND: Statins are strong inhibitors of cholesterol biosynthesis and help to prevent cardiovascular disease. They also exert additional pleiotropic effects that include an anti-inflammatory action and are independent of cholesterol, but the molecular mechanisms underlying these additional effects have remained unclear. We have now examined the effects of atorvastatin on cardiac and adipose tissue inflammation in DahlS.Z-Leprfa/Leprfa (DS/obese) rats, which we previously established as a model of metabolic syndrome (MetS). METHODS AND RESULTS: DS/obeserats were treated with atorvastatin (6 or 20mgkg-1day-1) from 9 to 13weeks of age. Atorvastatin ameliorated cardiac fibrosis, diastolic dysfunction, oxidative stress, and inflammation as well as adipose tissue inflammation in these animals at both doses. The high dose of atorvastatin reduced adipocyte hypertrophy to a greater extent than did the low dose. Atorvastatin inhibited the up-regulation of peroxisome proliferator-activated receptor γ gene expression in adipose tissue as well as decreased the serum adiponectin concentration in DS/obeserats. It also activated AMP-activated protein kinase (AMPK) as well as inactivated nuclear factor-κB (NF-κB) in the heart of these animals. The down-regulation of AMPK and NF-κB activities in adipose tissue of DS/obeserats was attenuated and further enhanced, respectively, by atorvastatin treatment. CONCLUSIONS: The present results suggest that the anti-inflammatory effects of atorvastatin on the heart and adipose tissue are attributable at least partly to increased AMPK activity and decreased NF-κB activity in this rat model of MetS.
Authors: Štefan Bezek; Zuzana Brnoliaková; Ružena Sotníková; Vladimír Knezl; Ema Paulovičová; Jana Navarová; Viktor Bauer Journal: Interdiscip Toxicol Date: 2018-02-14
Authors: Paolo Raggi; Varuna Gadiyaram; Chao Zhang; Zhengjia Chen; Gary Lopaschuk; Arthur E Stillman Journal: J Am Heart Assoc Date: 2019-06-13 Impact factor: 5.501