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PARP1 induces cardiac fibrosis by mediating mTOR activity.

Cardiac fibrosis is involved in nearly all forms of heart diseases, and is characterized by excessive deposition of extracellular matrix (ECM) proteins by cardiac fibroblasts (CFs). We and others have reported the possibility of poly(ADP-ribose) polymerase 1 (PARP1), the founding subtype of the PARPs enzyme family, as a novel therapeutic target of heart diseases. The cardiac fibrotic induction of mTOR (mammalian target of rapamycin) is mainly due to collagen expression, Smad3 and p53/JNK-mediated apoptosis. However, the possible link between PARP1 and mTOR in the progression of cardiac fibrosis remains unclear. In this study, PARP1 protein expression, and the activity of mTOR and its three target substrates (S6K1, 4E-BP and ULK1) were augmented; meanwhile, the NAD content was significantly reduced in the process of cardiac fibrosis in vivo and in vitro. SD rats were intraperitoneally injected with 3AB (20 mg/kg/d, a well-established PARP1 inhibitor) or rapamycin (Rapa, 1 mg/kg/d, used for mTOR inhibition) 7 days after AAC (abdominal aortic constriction) surgery for 6 weeks. Pre-treatment of 3AB or Rapa both relieved AAC-caused cardiac fibrosis and heart dysfunction. Overexpression of PARP1 with adenovirus carrying PARP1 gene (Ad-PARP1) specifically transduced into the hearts via intramyocardial multi-point injection caused similar myocardial damage. In CFs, pre-incubation with PARP1 or mTOR inhibitors all blocked TGF-β1-induced cardiac fibrosis. PARP1 overexpression evoked cardiac fibrosis, which could be antagonized by mTOR inhibitors or NAD supplementation in CFs. These results provide novel and compelling evidence that PARP1 exacerbated cardiac fibrosis, which was partially attributed to NAD-dependent activation of mTOR. This article is protected by copyright. All rights reserved.

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