title: PKD knockdown inhibits pressure overload-induced cardiac hypertrophy by promoting autophagy via AKT/mTOR pathway.
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 (2×108transducing 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.
authors.affiliation: Department of Oncology, Affiliated Hospital of Shandong Academy of Medical Sciences, Shandong, China.
authors.forename: Di
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Department of Cardiology, Shandong Provincial Chest Hospital, Shandong, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Jinan Central Hospital, Affiliated with Shandong University, Shandong, China.
authors.forename: Honghai
authors.initials: H
authors.lastname: Peng
authors.affiliation: Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Shandong, China.
authors.forename: Xiangjuan
authors.initials: X
authors.lastname: Liu
authors.affiliation: Shandong Academy of Medical Sciences, Shandong, China.
authors.forename: Weixing
authors.initials: W
authors.lastname: Guo
authors.affiliation: Department of Cardiology, Jinan Central Hospital, Affiliated with Shandong University, Shandong, China.
authors.forename: Guohai
authors.initials: G
authors.lastname: Su
authors.affiliation: Department of Cardiology, Jinan Central Hospital, Affiliated with Shandong University, Shandong, China.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Zhao
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D006332:Cardiomegaly / Q000209:etiology / Q000378:metabolism* / Q000628:therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011493:Protein Kinase C / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; C089212:protein kinase D; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D011493:Protein Kinase C; D020123:Sirolimus
keywords: AKT/mTOR pathway; PKD knockdown; autophagy; cardiac hypertrophy; pressure overload