Abstract 12376: Analysis of Novel Target Molecules of Nobiletin, a Potent Therapeutic Agent Against Heart Failure
Introduction: Maladaptive hypertrophy is being recognized as a critical event during the development of heart failure. We screened some natural compounds and found that nobiletin, contained in Citrus depressa, prevented the development of heart failure in rats with myocardial infarction. However, the target molecule of nobiletin in cardiomyocytes is still unclear.
Hypothesis: To solve this problem, we attempted to identify novel nobiletin-binding proteins by a proteomics approach and investigate its functional mechanism in mice.
Methods and Results: Nobiletin-binding proteins were purified from rat heart using biotin-conjugated nobiletin or biotin alone and identified by LC-LC/MS-MS. One of them, nobiletin-binding protein 1 (NBP1) which related to cellular metabolic pathway, physically bound to biotin-conjugated nobiletin by pull-down assay. Nobiletin also activated enzyme activity of NBP1 in vitro. In cardiomyocyte, knockdown of NBP1 failed to nobiletin-mediated anti-hypertrophic effect, and overexpression of NBP1 inhibited phenylephrine-induced ANF and ET-1 promoter activities and cardiomyocyte hypertrophy. TG mice carrying NBP1 gene under the CAG promoter and WT mice were subjected to sham or transarotic constriction (TAC). After 8 weeks, NBP1-TG mice resisted pressure-overload induced cardiac hypertrophy and systolic dysfunction compared to WT mice without affecting blood pressure. The quantitative mRNA analysis showed that TAC-induced ANF, BNP, and β-MHC gene transcriptions were reduced in left ventricle of NBP1-TG mice compared to those of WT mice.
Conclusions: Proteomics analysis on molecular targets of nobiletin is useful to delineate nobiletin-mediated signaling pathways and anti-hypertrophic effect in cardiomyocytes. These finding suggest that nobiletin inhibits cardiomyocyte hypertrophy and the development of heart failure through the functional regulation of NBP1 activity. A natural compound, Nobiletin, might be a candidate for heart failure agent in human.
Author Disclosures: Y. Sunagawa: None. S. Ogawahara: None. M. Funamoto: None. R. Sakurai: None. K. Hieda: None. Y. Katanasaka: None. T. Asakawa: None. T. Kan: None. A. Murakami: None. H. Wada: None. A. Murakami: None. K. Hasegawa: None. T. Morimoto: None.
- © 2015 by American Heart Association, Inc.