ISSN: 1449-2288International Journal of Biological Sciences
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Int J Biol Sci 2017; 13(3):276-285. doi:10.7150/ijbs.17617 This issue Cite
Research Paper
PKD knockdown inhibits pressure overload-induced cardiac hypertrophy by promoting autophagy via AKT/mTOR pathway
1. Department of Oncology, Affiliated Hospital of Shandong Academy of Medical Sciences, Shandong, China.
2. Department of Cardiology, Shandong Provincial Chest Hospital, Shandong, China.
3. Department of Anesthesiology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
4. Department of Cardiology, Jinan Central Hospital, Affiliated with Shandong University, Shandong, China.
5. Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Shandong, China.
6. Shandong Academy of Medical Sciences, Shandong, China.
Abstract
Growing evidence shows that protein kinase D (PKD) plays an important role in the development of pressure overload-induced cardiac hypertrophy. However, the mechanisms involved are not clear. This study tested our hypothesis that PKD might mediate cardiac hypertrophy by negatively regulating autophagy using the technique of PKD knockdown by siRNA. Cardiac hypertrophy was induced in 8-week old male C57BL/6 mice by transverse aortic constriction (TAC). TAC mice were then divided into five groups receiving the treatments of vehicle (DMSO), an autophagy inducer rapamycin (1 mg/kg/day, i.p.), control siRNA, lentiviral PKD siRNA (2×108 transducing units/0.1 ml, i.v. injection in one day after surgery, and repeated in 2 weeks after surgery), and PKD siRNA plus 3-methyladenine (3-MA, an autophagy inhibitor, 20 mg/kg/day, i.p.), respectively. Four weeks after TAC surgery, echocardiographic study, hematoxylin and eosin (HE) staining, and Masson's staining showed mice with TAC had significantly hypertrophy and remodeling compared with sham animals. Treatments with PKD siRNA or rapamycin significantly ameliorated the cardiac hypertrophy and dysfunction. Moreover, PKD siRNA increased cardiac autophagic activity determined by electron micrographic study and the biomarkers by Western blot, accompanied with the downregulated AKT/mTOR/S6K signaling pathway. All the cardiac effects of PDK knockdown were inhibited by co-treatment with 3-MA. These results suggest that PKD is involved in the development of cardiac hypertrophy by inhibiting cardiac autophagy via AKT/mTOR pathway.
Keywords: PKD knockdown, pressure overload, cardiac hypertrophy, autophagy, AKT/mTOR pathway
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