We previously reported that histone deacetylase 6 (HDAC6) has an important role in endothelial cell (EC) function in vitro. However, whether HDAC6 plays a role in atherogenesis in vivo and the mechanism(s) that control HDAC6 activity/expression in response to atherogenic stimuli are unclear. The goals of this study were to determine whether HDAC6 inhibitor tubacin attenuates atherogenesis and to elucidate specific molecular mechanism(s) that regulate endothelial HDAC6 expression/activity. We evaluated whether administration of tubacin attenuated or reversed the endothelial dysfunction and atherosclerosis induced in mice by a single intraperitoneal injection of adeno-associated viruses encoding liver-target PCSK9 gain-of-function mutant followed by a high fat diet (HFD) for 18 weeks. Tubacin significantly blunted PCSK9-induced increases in pulse wave velocity (index of vascular stiffness and overall vascular health) that are also seen in atherogenic mice. Furthermore, tubacin protected vessels from defective vasorelaxation, as evaluated by acetylcholine-mediated relaxation using wire myograph. Plaque burden defined by Oil Red O staining was also found to be significantly less in mice that received tubacin than in those that received PCSK9 alone. Inhibition of the NEDDylation pathway with MLN4924, an inhibitor of NEDD8-activating enzyme 1 (NAE1), significantly increased HDAC6 activity in HAECs. Interestingly, HDAC6 expression remained unchanged. Further, HAECs exposed to the atherogenic stimulus oxidized low-density lipoprotein (OxLDL) exhibited enhanced HDAC6 activity, which was attenuated by pretreatment with MLN4924. The HDAC6 NEDDylation molecular pathway might regulate genes related to endothelial control of vasomotor tone, reactivity, and atherosclerosis. Tubacin may represent a novel pharmacologic intervention for atherogenesis and other vasculopathies.
机构:
Univ Texas Hlth Sci Ctr San Antonio, Reg Acad Hlth Ctr, Div Med Res, Edinburg, TX 78541 USAUniv Texas Hlth Sci Ctr San Antonio, Reg Acad Hlth Ctr, Div Med Res, Edinburg, TX 78541 USA
Chang, Fang-Mei
Reyna, Sara M.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Texas Hlth Sci Ctr San Antonio, Reg Acad Hlth Ctr, Div Med Res, Edinburg, TX 78541 USA
Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Diabet, San Antonio, TX 78229 USAUniv Texas Hlth Sci Ctr San Antonio, Reg Acad Hlth Ctr, Div Med Res, Edinburg, TX 78541 USA
Reyna, Sara M.
Granados, Jose C.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Texas Hlth Sci Ctr San Antonio, Reg Acad Hlth Ctr, Div Med Res, Edinburg, TX 78541 USAUniv Texas Hlth Sci Ctr San Antonio, Reg Acad Hlth Ctr, Div Med Res, Edinburg, TX 78541 USA
Granados, Jose C.
Wei, Sung-Jen
论文数: 0引用数: 0
h-index: 0
机构:
Univ Texas Hlth Sci Ctr San Antonio, Reg Acad Hlth Ctr, Div Med Res, Edinburg, TX 78541 USA
Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USAUniv Texas Hlth Sci Ctr San Antonio, Reg Acad Hlth Ctr, Div Med Res, Edinburg, TX 78541 USA
Wei, Sung-Jen
Innis-Whitehouse, Wendy
论文数: 0引用数: 0
h-index: 0
机构:
Univ Texas Hlth Sci Ctr San Antonio, Reg Acad Hlth Ctr, Div Med Res, Edinburg, TX 78541 USAUniv Texas Hlth Sci Ctr San Antonio, Reg Acad Hlth Ctr, Div Med Res, Edinburg, TX 78541 USA
Innis-Whitehouse, Wendy
Maffi, Shivani K.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Texas Hlth Sci Ctr San Antonio, Reg Acad Hlth Ctr, Div Med Res, Edinburg, TX 78541 USA
Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, San Antonio, TX 78245 USAUniv Texas Hlth Sci Ctr San Antonio, Reg Acad Hlth Ctr, Div Med Res, Edinburg, TX 78541 USA
Maffi, Shivani K.
Rodriguez, Edward
论文数: 0引用数: 0
h-index: 0
机构:
Univ Texas Hlth Sci Ctr San Antonio, Reg Acad Hlth Ctr, Div Med Res, Edinburg, TX 78541 USAUniv Texas Hlth Sci Ctr San Antonio, Reg Acad Hlth Ctr, Div Med Res, Edinburg, TX 78541 USA
Rodriguez, Edward
Slaga, Thomas J.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USAUniv Texas Hlth Sci Ctr San Antonio, Reg Acad Hlth Ctr, Div Med Res, Edinburg, TX 78541 USA
Slaga, Thomas J.
Short, John D.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Texas Hlth Sci Ctr San Antonio, Reg Acad Hlth Ctr, Div Med Res, Edinburg, TX 78541 USA
Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USAUniv Texas Hlth Sci Ctr San Antonio, Reg Acad Hlth Ctr, Div Med Res, Edinburg, TX 78541 USA
机构:
Thomas Jefferson Univ, Ctr Translat Med, 1020 Locust St,Rm 368G, Philadelphia, PA 19107 USA
Shanghai Jiao Tong Univ, Sch Med, Xinhua Hosp, Dept Pharm, Shanghai 200092, Peoples R ChinaThomas Jefferson Univ, Ctr Translat Med, 1020 Locust St,Rm 368G, Philadelphia, PA 19107 USA
Chen, Jihui
Zhang, Jian
论文数: 0引用数: 0
h-index: 0
机构:
Shanghai Jiao Tong Univ, Sch Med, Xinhua Hosp, Dept Pharm, Shanghai 200092, Peoples R ChinaThomas Jefferson Univ, Ctr Translat Med, 1020 Locust St,Rm 368G, Philadelphia, PA 19107 USA
Zhang, Jian
Shaik, Noor F.
论文数: 0引用数: 0
h-index: 0
机构:
Thomas Jefferson Univ, Dept Med, Cardeza Ctr Vasc Biol, Philadelphia, PA 19107 USAThomas Jefferson Univ, Ctr Translat Med, 1020 Locust St,Rm 368G, Philadelphia, PA 19107 USA
Shaik, Noor F.
Yi, Bing
论文数: 0引用数: 0
h-index: 0
机构:
Thomas Jefferson Univ, Ctr Translat Med, 1020 Locust St,Rm 368G, Philadelphia, PA 19107 USAThomas Jefferson Univ, Ctr Translat Med, 1020 Locust St,Rm 368G, Philadelphia, PA 19107 USA
Yi, Bing
Wei, Xin
论文数: 0引用数: 0
h-index: 0
机构:
Shanghai Jiao Tong Univ, Sch Med, Xinhua Hosp, Dept Pharm, Shanghai 200092, Peoples R ChinaThomas Jefferson Univ, Ctr Translat Med, 1020 Locust St,Rm 368G, Philadelphia, PA 19107 USA
Wei, Xin
Yang, Xiao-Feng
论文数: 0引用数: 0
h-index: 0
机构:
Temple Univ, Ctr Metab Dis Res, Lewis Katz Sch Med, Philadelphia, PA 19107 USAThomas Jefferson Univ, Ctr Translat Med, 1020 Locust St,Rm 368G, Philadelphia, PA 19107 USA
Yang, Xiao-Feng
Naik, Ulhas P.
论文数: 0引用数: 0
h-index: 0
机构:
Thomas Jefferson Univ, Dept Med, Cardeza Ctr Vasc Biol, Philadelphia, PA 19107 USAThomas Jefferson Univ, Ctr Translat Med, 1020 Locust St,Rm 368G, Philadelphia, PA 19107 USA
Naik, Ulhas P.
Summer, Ross
论文数: 0引用数: 0
h-index: 0
机构:
Thomas Jefferson Univ, Ctr Translat Med, 1020 Locust St,Rm 368G, Philadelphia, PA 19107 USAThomas Jefferson Univ, Ctr Translat Med, 1020 Locust St,Rm 368G, Philadelphia, PA 19107 USA
Summer, Ross
Yan, Guijun
论文数: 0引用数: 0
h-index: 0
机构:
Nanjing Univ, Sch Med, Affiliated Drum Tower Hosp, Reprod Med Ctr, Nanjing 210023, Jiangsu, Peoples R ChinaThomas Jefferson Univ, Ctr Translat Med, 1020 Locust St,Rm 368G, Philadelphia, PA 19107 USA
Yan, Guijun
Xu, Xinyun
论文数: 0引用数: 0
h-index: 0
机构:
Second Mil Med Univ, Shanghai Changzheng Hosp, Dept Gen Surg, Shanghai 200003, Peoples R ChinaThomas Jefferson Univ, Ctr Translat Med, 1020 Locust St,Rm 368G, Philadelphia, PA 19107 USA
Xu, Xinyun
Sun, Jianxin
论文数: 0引用数: 0
h-index: 0
机构:
Thomas Jefferson Univ, Ctr Translat Med, 1020 Locust St,Rm 368G, Philadelphia, PA 19107 USAThomas Jefferson Univ, Ctr Translat Med, 1020 Locust St,Rm 368G, Philadelphia, PA 19107 USA
机构:
St Jude Childrens Res Hosp, Dept Biol Struct, Memphis, TN 38105 USA
St Jude Childrens Res Hosp, Howard Hughes Med Inst, Memphis, TN 38105 USAETH, Inst Biochem, Dept Biol, CH-8093 Zurich, Switzerland
机构:
Univ Texas Hlth Sci Ctr San Antonio, Reg Acad Hlth Ctr, Div Med Res, Edinburg, TX 78541 USAUniv Texas Hlth Sci Ctr San Antonio, Reg Acad Hlth Ctr, Div Med Res, Edinburg, TX 78541 USA
Chang, Fang-Mei
Reyna, Sara M.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Texas Hlth Sci Ctr San Antonio, Reg Acad Hlth Ctr, Div Med Res, Edinburg, TX 78541 USA
Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Diabet, San Antonio, TX 78229 USAUniv Texas Hlth Sci Ctr San Antonio, Reg Acad Hlth Ctr, Div Med Res, Edinburg, TX 78541 USA
Reyna, Sara M.
Granados, Jose C.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Texas Hlth Sci Ctr San Antonio, Reg Acad Hlth Ctr, Div Med Res, Edinburg, TX 78541 USAUniv Texas Hlth Sci Ctr San Antonio, Reg Acad Hlth Ctr, Div Med Res, Edinburg, TX 78541 USA
Granados, Jose C.
Wei, Sung-Jen
论文数: 0引用数: 0
h-index: 0
机构:
Univ Texas Hlth Sci Ctr San Antonio, Reg Acad Hlth Ctr, Div Med Res, Edinburg, TX 78541 USA
Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USAUniv Texas Hlth Sci Ctr San Antonio, Reg Acad Hlth Ctr, Div Med Res, Edinburg, TX 78541 USA
Wei, Sung-Jen
Innis-Whitehouse, Wendy
论文数: 0引用数: 0
h-index: 0
机构:
Univ Texas Hlth Sci Ctr San Antonio, Reg Acad Hlth Ctr, Div Med Res, Edinburg, TX 78541 USAUniv Texas Hlth Sci Ctr San Antonio, Reg Acad Hlth Ctr, Div Med Res, Edinburg, TX 78541 USA
Innis-Whitehouse, Wendy
Maffi, Shivani K.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Texas Hlth Sci Ctr San Antonio, Reg Acad Hlth Ctr, Div Med Res, Edinburg, TX 78541 USA
Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, San Antonio, TX 78245 USAUniv Texas Hlth Sci Ctr San Antonio, Reg Acad Hlth Ctr, Div Med Res, Edinburg, TX 78541 USA
Maffi, Shivani K.
Rodriguez, Edward
论文数: 0引用数: 0
h-index: 0
机构:
Univ Texas Hlth Sci Ctr San Antonio, Reg Acad Hlth Ctr, Div Med Res, Edinburg, TX 78541 USAUniv Texas Hlth Sci Ctr San Antonio, Reg Acad Hlth Ctr, Div Med Res, Edinburg, TX 78541 USA
Rodriguez, Edward
Slaga, Thomas J.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USAUniv Texas Hlth Sci Ctr San Antonio, Reg Acad Hlth Ctr, Div Med Res, Edinburg, TX 78541 USA
Slaga, Thomas J.
Short, John D.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Texas Hlth Sci Ctr San Antonio, Reg Acad Hlth Ctr, Div Med Res, Edinburg, TX 78541 USA
Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USAUniv Texas Hlth Sci Ctr San Antonio, Reg Acad Hlth Ctr, Div Med Res, Edinburg, TX 78541 USA
机构:
Thomas Jefferson Univ, Ctr Translat Med, 1020 Locust St,Rm 368G, Philadelphia, PA 19107 USA
Shanghai Jiao Tong Univ, Sch Med, Xinhua Hosp, Dept Pharm, Shanghai 200092, Peoples R ChinaThomas Jefferson Univ, Ctr Translat Med, 1020 Locust St,Rm 368G, Philadelphia, PA 19107 USA
Chen, Jihui
Zhang, Jian
论文数: 0引用数: 0
h-index: 0
机构:
Shanghai Jiao Tong Univ, Sch Med, Xinhua Hosp, Dept Pharm, Shanghai 200092, Peoples R ChinaThomas Jefferson Univ, Ctr Translat Med, 1020 Locust St,Rm 368G, Philadelphia, PA 19107 USA
Zhang, Jian
Shaik, Noor F.
论文数: 0引用数: 0
h-index: 0
机构:
Thomas Jefferson Univ, Dept Med, Cardeza Ctr Vasc Biol, Philadelphia, PA 19107 USAThomas Jefferson Univ, Ctr Translat Med, 1020 Locust St,Rm 368G, Philadelphia, PA 19107 USA
Shaik, Noor F.
Yi, Bing
论文数: 0引用数: 0
h-index: 0
机构:
Thomas Jefferson Univ, Ctr Translat Med, 1020 Locust St,Rm 368G, Philadelphia, PA 19107 USAThomas Jefferson Univ, Ctr Translat Med, 1020 Locust St,Rm 368G, Philadelphia, PA 19107 USA
Yi, Bing
Wei, Xin
论文数: 0引用数: 0
h-index: 0
机构:
Shanghai Jiao Tong Univ, Sch Med, Xinhua Hosp, Dept Pharm, Shanghai 200092, Peoples R ChinaThomas Jefferson Univ, Ctr Translat Med, 1020 Locust St,Rm 368G, Philadelphia, PA 19107 USA
Wei, Xin
Yang, Xiao-Feng
论文数: 0引用数: 0
h-index: 0
机构:
Temple Univ, Ctr Metab Dis Res, Lewis Katz Sch Med, Philadelphia, PA 19107 USAThomas Jefferson Univ, Ctr Translat Med, 1020 Locust St,Rm 368G, Philadelphia, PA 19107 USA
Yang, Xiao-Feng
Naik, Ulhas P.
论文数: 0引用数: 0
h-index: 0
机构:
Thomas Jefferson Univ, Dept Med, Cardeza Ctr Vasc Biol, Philadelphia, PA 19107 USAThomas Jefferson Univ, Ctr Translat Med, 1020 Locust St,Rm 368G, Philadelphia, PA 19107 USA
Naik, Ulhas P.
Summer, Ross
论文数: 0引用数: 0
h-index: 0
机构:
Thomas Jefferson Univ, Ctr Translat Med, 1020 Locust St,Rm 368G, Philadelphia, PA 19107 USAThomas Jefferson Univ, Ctr Translat Med, 1020 Locust St,Rm 368G, Philadelphia, PA 19107 USA
Summer, Ross
Yan, Guijun
论文数: 0引用数: 0
h-index: 0
机构:
Nanjing Univ, Sch Med, Affiliated Drum Tower Hosp, Reprod Med Ctr, Nanjing 210023, Jiangsu, Peoples R ChinaThomas Jefferson Univ, Ctr Translat Med, 1020 Locust St,Rm 368G, Philadelphia, PA 19107 USA
Yan, Guijun
Xu, Xinyun
论文数: 0引用数: 0
h-index: 0
机构:
Second Mil Med Univ, Shanghai Changzheng Hosp, Dept Gen Surg, Shanghai 200003, Peoples R ChinaThomas Jefferson Univ, Ctr Translat Med, 1020 Locust St,Rm 368G, Philadelphia, PA 19107 USA
Xu, Xinyun
Sun, Jianxin
论文数: 0引用数: 0
h-index: 0
机构:
Thomas Jefferson Univ, Ctr Translat Med, 1020 Locust St,Rm 368G, Philadelphia, PA 19107 USAThomas Jefferson Univ, Ctr Translat Med, 1020 Locust St,Rm 368G, Philadelphia, PA 19107 USA
机构:
St Jude Childrens Res Hosp, Dept Biol Struct, Memphis, TN 38105 USA
St Jude Childrens Res Hosp, Howard Hughes Med Inst, Memphis, TN 38105 USAETH, Inst Biochem, Dept Biol, CH-8093 Zurich, Switzerland