Curcumin attenuates cardiac fibrosis in spontaneously hypertensive rats through PPAR-γ activation
Abstract
Zhe MENG1, #, Xin-hui YU2, #, Jun CHEN1, Ling LI1, *, Sheng LI2, *
1Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; 2Department of Thoracic Surgery, Taicang Affiliated Hospital of Soochow University, Taicang 215400, China
Aim: To investigate the effects of curcumin (Cur) on cardiac fibrosis in spontaneously hypertensive rats (SHRs) and the mechanisms underlying the anti-fibrotic effect of Cur in rat cardiac fibroblasts (CFs) in vitro.
Methods: SHRs were orally treated with Cur (100 mg·kg-1·d-1) or Cur (100 mg·kg-1·d-1) plus the PPAR-γ antagonist GW9662 (1 mg·kg-1·d-1) for 12 weeks. Cultured CFs were treated with angiotensin II (Ang II, 0.1 μmol/L) in vitro. The expression of relevant proteins and mRNAs was analyzed using Western blotting and real-time PCR, respectively. The expression and activity of peroxisome proliferator-activated receptor-γ (PPAR-γ) were detected using Western blotting and a DNA-binding assay, respectively.
Results: Treatment of SHRs with Cur significantly decreased systolic blood pressure, blood Ang II concentration, heart weight/body weight ratio and left ventricle weight/body weight ratio, with concurrently decreased expression of connective tissue growth factor (CTGF), plasminogen activator inhibitor (PAI)-1, collagen III (Col III) and fibronectin (FN), and increased expression and activity of PPAR-γ in the left ventricle. Co-treatment with GW9662 partially abrogated the anti-fibrotic effects of Cur in SHRs. Pretreatment of CFs with Cur (5, 10, 20 μmol/L) dose-dependently inhibited Ang II-induced expression of CTGF, PAI-1, Col III and FN, and increased the expression and binding activity of PPAR-γ. Pretreatment with GW9662 partially reversed anti-fibrotic effects of Cur in vitro. Furthermore, pretreatment of CFs with Cur inhibited Ang II-induced expression of transforming growth factor-β1 (TGF-β1) and phosphorylation of Smad2/3, which were reversed by GW9662.
Conclusion: Cur attenuates cardiac fibrosis in SHRs and inhibits Ang II-induced production of CTGF, PAI-1 and ECM in CFs in vitro. The crosstalk between PPAR-γ and TGF-β1/Smad2/3 signaling is involved in the anti-fibrotic and anti-proliferative effects of Cur.
Keywords: hypertension; cardiac fibrosis; curcumin; angiotensin II; GW9662; connective tissue growth factor; plasminogen activator inhibitor-1; PPAR-γ; Smad2/3
This study was supported by the Youth Foundation of The First Affiliated Hospital of Zhengzhou University [YFFAHZZ 2013020105 to Zhe MENG].
# The first two authors contributed equally to this paper.
* To whom correspondence should be addressed.
E-mail liling63035@sina.com (Ling LI); lisheng_0512@126.com (Sheng LI)
Received 2014-01-01 Accepted 2014-06-05
Keywords:
1Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; 2Department of Thoracic Surgery, Taicang Affiliated Hospital of Soochow University, Taicang 215400, China
Aim: To investigate the effects of curcumin (Cur) on cardiac fibrosis in spontaneously hypertensive rats (SHRs) and the mechanisms underlying the anti-fibrotic effect of Cur in rat cardiac fibroblasts (CFs) in vitro.
Methods: SHRs were orally treated with Cur (100 mg·kg-1·d-1) or Cur (100 mg·kg-1·d-1) plus the PPAR-γ antagonist GW9662 (1 mg·kg-1·d-1) for 12 weeks. Cultured CFs were treated with angiotensin II (Ang II, 0.1 μmol/L) in vitro. The expression of relevant proteins and mRNAs was analyzed using Western blotting and real-time PCR, respectively. The expression and activity of peroxisome proliferator-activated receptor-γ (PPAR-γ) were detected using Western blotting and a DNA-binding assay, respectively.
Results: Treatment of SHRs with Cur significantly decreased systolic blood pressure, blood Ang II concentration, heart weight/body weight ratio and left ventricle weight/body weight ratio, with concurrently decreased expression of connective tissue growth factor (CTGF), plasminogen activator inhibitor (PAI)-1, collagen III (Col III) and fibronectin (FN), and increased expression and activity of PPAR-γ in the left ventricle. Co-treatment with GW9662 partially abrogated the anti-fibrotic effects of Cur in SHRs. Pretreatment of CFs with Cur (5, 10, 20 μmol/L) dose-dependently inhibited Ang II-induced expression of CTGF, PAI-1, Col III and FN, and increased the expression and binding activity of PPAR-γ. Pretreatment with GW9662 partially reversed anti-fibrotic effects of Cur in vitro. Furthermore, pretreatment of CFs with Cur inhibited Ang II-induced expression of transforming growth factor-β1 (TGF-β1) and phosphorylation of Smad2/3, which were reversed by GW9662.
Conclusion: Cur attenuates cardiac fibrosis in SHRs and inhibits Ang II-induced production of CTGF, PAI-1 and ECM in CFs in vitro. The crosstalk between PPAR-γ and TGF-β1/Smad2/3 signaling is involved in the anti-fibrotic and anti-proliferative effects of Cur.
Keywords: hypertension; cardiac fibrosis; curcumin; angiotensin II; GW9662; connective tissue growth factor; plasminogen activator inhibitor-1; PPAR-γ; Smad2/3
This study was supported by the Youth Foundation of The First Affiliated Hospital of Zhengzhou University [YFFAHZZ 2013020105 to Zhe MENG].
# The first two authors contributed equally to this paper.
* To whom correspondence should be addressed.
E-mail liling63035@sina.com (Ling LI); lisheng_0512@126.com (Sheng LI)
Received 2014-01-01 Accepted 2014-06-05