Abstract 12237: Upregulation of Cardiac MicroRNA 34a, Sirt1, and Notch1 Following Oral Ingestion of Beetroot Juice and Doxorubicin Treatment: A Novel Protective Signaling Against Cardiotoxicity
Background: Beetroot juice (BRJ) is a dietary supplement containing high levels of nitrate and other nutrients. We previously reported that oral intake of BRJ protects against cardiotoxicity of doxorubicin (DOX) - a commonly used anticancer drug. BRJ diminished cell injury (indicated by serum level of cardiac troponin I) and ventricular dysfunction caused by DOX. The present study furhter investigates if BRJ modulates microRNA 34a (miR34a), a potent endogenous tumor suppressive molecule and its putative protein targets including Sirt1 (a well identified cardioprotective protein) and Notch1 (a major receptor for Notch signaling pathway that controls cell fate decision, including cell differentiation, proliferation, and death).
Methods & Results: Adult male CF-1 mice were divided into 4 groups (n=3-4/group): 1. Saline (0.2 ml, IP); 2. DOX (15 mg/kg, IP); 3. BRJ (10 g BRJ extract was added into 1 liter of drinking water and provided for 13 days); and 4. BRJ+DOX (mice received BRJ for 7 days before DOX injection and during the post-DOX period. Five days after DOX or saline injection, heart tissue samples were collected and processed for real-time PCR or Western blot analyses. Cardiac expression of miR34a was significantly enhanced by BRJ only in DOX-treated hearts (P<0.01, Fig. A). Interestingly, BRJ intake also significantly augmented both mRNA and protein expression levels of Sirt1 (Fig. B & C) and Notch1 (Fig. D & E), especially when co-treated with DOX (BRJ+DOX; P<0.01 versus Control or DOX group, respectively).
Conclusions: BRJ intake upregulates cardiac miR34a expression with concomitant enhancement of Sirt1 and Notch1 mRNA/protein expression, which may contribute to BRJ-induced protection against DOX cardiotoxicity. These novel molecular mechanisms further suggest that the anti-cancer and cardioprotective dual properties of BRJ can be utilized as an effective nutraceutical therapy for reducing heart damages in cancer patients undergoing DOX chemotherapy.
Author Disclosures: C. Yin: None. S. Rehman: None. R.C. Kukreja: None. L. Xi: None.
- © 2014 by American Heart Association, Inc.