title: Attenuation of cardiac hypertrophy by inhibiting both mTOR and NFkappaB activation in vivo.
abstract: A role for the PI3K/Akt/mTOR pathway in cardiac hypertrophy has been well documented. We reported that NFkappaB activation is needed for cardiac hypertrophy in vivo. To investigate whether both NFkappaB activation and PI3K/Akt/mTOR signaling participate in the development of cardiac hypertrophy, two models of cardiac hypertrophy, namely, induction in caAkt-transgenic mice and by aortic banding in mice, were employed. Rapamycin (2 mg/kg/daily), an inhibitor of the mammalian target of rapamycin, and the antioxidant pyrrolidine dithiocarbamate (PDTC; 120 mg/kg/daily), which can inhibit NFkappaB activation, were administered to caAkt mice at 8 weeks of age for 2 weeks. Both rapamycin and PDTC were also administered to the mice immediately after aortic banding for 2 weeks. Administration of either rapamycin or PDTC separately or together to caAkt mice reduced the ratio of heart weight/body weight by 21.54, 32.68, and 42.07% compared with untreated caAkt mice. PDTC administration significantly reduced cardiac NFkappaB activation by 46.67% and rapamycin significantly decreased the levels of p70S6K by 34.20% compared with untreated caAkt mice. Similar results were observed in aortic-banding-induced cardiac hypertrophy in mice. Our results suggest that both NFkappaB activation and the PI3K/Akt signaling pathway participate in the development of cardiac hypertrophy in vivo.
authors.affiliation: Department of Surgery, Campus Box 70575, East Tennessee State University, Johnson City, TN 37614, USA.
authors.forename: Tuanzhu
authors.initials: T
authors.lastname: Ha
authors.forename: Yuehua
authors.initials: Y
authors.lastname: Li
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.forename: Julie R
authors.initials: JR
authors.lastname: McMullen
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Shioi
authors.forename: Seigo
authors.initials: S
authors.lastname: Izumo
authors.forename: Jim L
authors.initials: JL
authors.lastname: Kelley
authors.forename: Aiqiu
authors.initials: A
authors.lastname: Zhao
authors.forename: Georges E
authors.initials: GE
authors.lastname: Haddad
authors.forename: David L
authors.initials: DL
authors.lastname: Williams
authors.forename: I William
authors.initials: IW
authors.lastname: Browder
authors.forename: Race L
authors.initials: RL
authors.lastname: Kao
authors.forename: Chuanfu
authors.initials: C
authors.lastname: Li
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D006332:Cardiomegaly / Q000188:drug therapy* / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009929:Organ Size / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D013859:Thiocarbamates / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D011759:Pyrrolidines; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; C546843:mTOR protein, mouse