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Arjunolic acid, a peroxisome proliferator-activated receptor ? agonist, regresses cardiac fibrosis by inhibiting non-canonical TGF-? signaling.

ABSTRACT: Cardiac hypertrophy and associated heart fibrosis remain a major cause of death worldwide. Phytochemicals have gained attention as alternative therapeutics for managing cardiovascular diseases. These include the extract from the plant Terminalia arjuna, which is a popular cardioprotectant and may prevent or slow progression of pathological hypertrophy to heart failure. Here, we investigated the mode of action of a principal bioactive T. arjuna compound, arjunolic acid (AA), in ameliorating hemodynamic load-induced cardiac fibrosis and identified its intracellular target. Our data revealed that AA significantly represses collagen expression and improves cardiac function during hypertrophy. We found that AA binds to and stabilizes the ligand-binding domain of peroxisome proliferator-activated receptor ? (PPAR?) and increases its expression during cardiac hypertrophy. PPAR? knockdown during AA treatment in hypertrophy samples, including angiotensin II-treated adult cardiac fibroblasts and renal artery-ligated rat heart, suggests that AA-driven cardioprotection primarily arises from PPAR? agonism. Moreover, AA-induced PPAR? up-regulation leads to repression of TGF-? signaling, specifically by inhibiting TGF-?-activated kinase1 (TAK1) phosphorylation. We observed that PPAR? directly interacts with TAK1, predominantly via PPAR? N-terminal transactivation domain (AF-1) thereby masking the TAK1 kinase domain. The AA-induced PPAR?-bound TAK1 level thereby shows inverse correlation with the phosphorylation level of TAK1 and subsequent reduction in p38 MAPK and NF-?Bp65 activation, ultimately culminating in amelioration of excess collagen synthesis in cardiac hypertrophy. In conclusion, our findings unravel the mechanism of AA action in regressing hypertrophy-associated cardiac fibrosis by assigning a role of AA as a PPAR? agonist that inactivates non-canonical TGF-? signaling.

SUBMITTER: Bansal T

PROVIDER: S-EPMC5633106 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Arjunolic acid, a peroxisome proliferator-activated receptor α agonist, regresses cardiac fibrosis by inhibiting non-canonical TGF-β signaling.

Bansal Trisha T Chatterjee Emeli E Singh Jasdeep J Ray Arjun A Kundu Bishwajit B Thankamani V V Sengupta Shantanu S Sarkar Sagartirtha S

The Journal of biological chemistry 20170818 40

Cardiac hypertrophy and associated heart fibrosis remain a major cause of death worldwide. Phytochemicals have gained attention as alternative therapeutics for managing cardiovascular diseases. These include the extract from the plant <i>Terminalia arjuna,</i> which is a popular cardioprotectant and may prevent or slow progression of pathological hypertrophy to heart failure. Here, we investigated the mode of action of a principal bioactive <i>T. arjuna</i> compound, arjunolic acid (AA), in amel ...[more]

PMID: 28821620

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Dataset Information

Arjunolic acid, a peroxisome proliferator-activated receptor ? agonist, regresses cardiac fibrosis by inhibiting non-canonical TGF-? signaling.

Publications

Arjunolic acid, a peroxisome proliferator-activated receptor α agonist, regresses cardiac fibrosis by inhibiting non-canonical TGF-β signaling.

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