To determine whether endothelial Akt could affect vascular lesion formation, mutant mice with a constitutively active Akt transgene, which could be inducibly targeted to the vascular endothelium using the tet-off system (EC-Akt Tg mice), were generated. After withdrawal of doxycycline, EC-Akt Tg mice demonstrated increased endothelial-specific Akt activity and NO production. After blood flow cessation caused by carotid artery ligation, neointimal formation was attenuated in induced EC-Akt Tg mice compared with noninduced EC-Akt Tg mice and control littermates. To determine the role of eNOS in mediating these effects, mice were treated with Nω-nitro-L-arginine methyl ester (L-NAME). Neointimal formation was attenuated to a lesser extent in induced EC-Akt Tg mice treated with L-NAME, suggesting that some of the vascular protective effects were NO independent. Indeed, endothelial activation of Akt resulted in less EC apoptosis in ligated arteries. Immunostaining demonstrated decreased inflammatory and proliferative changes in induced EC-Akt Tg mice after vascular injury. These findings indicate that endothelial activation of Akt suppresses lesion formation via increased NO production, preservation of functional endothelial layer, and suppression of inflammatory and proliferative changes in the vascular wall. These results suggest that enhancing endothelial Akt activity alone could have therapeutic benefits after vascular injury.
Yasushi Mukai, Yoshiyuki Rikitake, Ichiro Shiojima, Sebastian Wolfrum, Minoru Satoh, Kyosuke Takeshita, Yukio Hiroi, Salvatore Salomone, Hyung-Hwan Kim, Laura E. Benjamin, Kenneth Walsh, James K. Liao
Title and authors | Publication | Year |
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CDCP1 knockdown suppresses PDGFRβ/AKT pathway-mediated vascular smooth muscle cell proliferation by inhibiting PDGFRβ endocytosis
Ji X, Wang X, Dong Q, Li W, Zhou N, Yue X, Zhao D, Yang X |
PeerJ | 2025 |
The Role of Oxidants in Percutaneous Coronary Intervention-Induced Endothelial Dysfunction: Can We Harness Redox Signaling to Improve Clinical Outcomes?
Wolhuter K, Kong SMY, Stanley CP, Kovacic JC |
Antioxidants & Redox Signaling | 2023 |
Favine/CCDC3 deficiency accelerated atherosclerosis and thrombus formation is associated with decreased MEF2C-KLF2 pathway
Kobayashi S, Kita S, Okuzaki D, Fujishima Y, Otsuki M, Kato H, Nishizawa Y, Miyashita K, Yokoyama C, Fukuhara A, Morii E, Shimomura I |
iScience | 2022 |
Protein kinase N2 mediates flow-induced eNOS activation and vascular tone regulation
Young-June Jin, Ramesh Chennupati, Rui Li, Guozheng Liang, ShengPeng Wang, András Iring, Johannes Graumann, Nina Wettschureck, Stefan Offermanns |
Journal of Clinical Investigation | 2021 |
Multifaceted Mechanisms of Action of Metformin Which Have Been Unraveled One after Another in the Long History
H Kaneto, T Kimura, A Obata, M Shimoda, K Kaku |
International journal of molecular sciences | 2021 |
Phosphorylation of Akt at Thr308 regulates p‐eNOS Ser1177 during physiological conditions
X Liang, R Wang, Y Guo, Z Cheng, D Lv, M Luo, A He, S Luo, Y Xia, J Kobarg |
FEBS Open Bio | 2021 |
Unexpected Pleiotropic Effects of SGLT2 Inhibitors: Pearls and Pitfalls of This Novel Antidiabetic Class
H Kaneto, A Obata, T Kimura, M Shimoda, T Kinoshita, T Matsuoka, K Kaku |
International journal of molecular sciences | 2021 |
Gab2 (Grb2-Associated Binder2) Plays a Crucial Role in Inflammatory Signaling and Endothelial Dysfunction
V Kondreddy, J Magisetty, S Keshava, LV Rao, UR Pendurthi |
Arteriosclerosis, thrombosis, and vascular biology | 2021 |
Utilizing Network Pharmacology to Explore the Possible Mechanism of Coptidis Rhizoma in Kawasaki Disease
X Fan, X Guo, Y Li, M Xu |
Frontiers in Pediatrics | 2021 |
Notable Underlying Mechanism for Pancreatic β-Cell Dysfunction and Atherosclerosis: Pleiotropic Roles of Incretin and Insulin Signaling
H Kaneto, A Obata, T Kimura, M Shimoda, J Sanada, Y Fushimi, N Katakami, T Matsuoka, K Kaku |
International journal of molecular sciences | 2020 |
Vascular endothelial PDPK1 plays a pivotal role in the maintenance of pancreatic beta cell mass and function in adult male mice
A Obata, T Kimura, Y Obata, M Shimoda, T Kinoshita, K Kohara, S Okauchi, H Hirukawa, S Kamei, S Nakanishi, T Mune, K Kaku, H Kaneto |
Diabetologia | 2019 |
The unconventional role of Akt1 in the advanced cancers and in diabetes-promoted carcinogenesis
A Alwhaibi, A Verma, MS Adil, PR Somanath |
Pharmacological research : the official journal of the Italian Pharmacological Society | 2019 |
Endothelial Cell Autonomous Role of Akt1: Regulation of Vascular Tone and Ischemia-Induced Arteriogenesis
MY Lee, A Gamez-Mendez, J Zhang, Z Zhuang, DJ Vinyard, J Kraehling, H Velazquez, GW Brudvig, TR Kyriakides, M Simons, WC Sessa |
Arteriosclerosis, thrombosis, and vascular biology | 2018 |
Lysyl oxidase (LOX) limits VSMC proliferation and neointimal thickening through its extracellular enzymatic activity
S Varona, M Orriols, M Galán, A Guadall, L Cañes, S Aguiló, M Sirvent, J Martínez-González, C Rodríguez |
Scientific Reports | 2018 |
Endothelial Akt1 loss promotes prostate cancer metastasis via β-catenin-regulated tight-junction protein turnover
F Gao, A Alwhaibi, S Artham, A Verma, PR Somanath |
British Journal of Cancer | 2018 |
Gene-Centric Analysis of Preeclampsia Identifies Maternal Association at PLEKHG1 Novelty and Significance
KJ Gray, VP Kovacheva, H Mirzakhani, AC Bjonnes, B Almoguera, AT DeWan, EW Triche, AF Saftlas, J Hoh, DL Bodian, E Klein, KC Huddleston, SA Ingles, CJ Lockwood, H Hakonarson, TF McElrath, JC Murray, ML Wilson, ER Norwitz, SA Karumanchi, BT Bateman, BJ Keating, R Saxena |
Hypertension | 2018 |
H-Ras Isoform Mediates Protection Against Pressure Overload–Induced Cardiac Dysfunction in Part Through Activation of AKTCLINICAL PERSPECTIVE
T Matsuda, JI Jeong, S Ikeda, T Yamamoto, S Gao, GJ Babu, P Zhai, DP Re |
Circulation. Heart failure | 2017 |
AKT/PKB Signaling: Navigating the Network
BD Manning, A Toker |
Cell | 2017 |
Modulation of long-term endothelial-barrier integrity is conditional to the cross-talk between Akt and Src signaling
F Gao, H Sabbineni, S Artham, PR Somanath |
Journal of Cellular Physiology | 2017 |
Akt1 promotes stimuli-induced endothelial-barrier protection through FoxO-mediated tight-junction protein turnover
F Gao, S Artham, H Sabbineni, A Al-Azayzih, XD Peng, N Hay, RH Adams, TV Byzova, PR Somanath |
Cellular and Molecular Life Sciences | 2016 |
Akt isoforms in vascular disease
H Yu, T Littlewood, M Bennett |
Vascular Pharmacology | 2015 |
Constitutively Active Akt1 Cooperates with KRasG12D to Accelerate In Vivo Pancreatic Tumor Onset and Progression
TM Albury, V Pandey, SB Gitto, L Dominguez, LP Spinel, J Talarchek, AJ Klein-Szanto, JR Testa, DA Altomare |
Neoplasia (New York, N.Y.) | 2015 |
Genetic Evidence Supports a Major Role for Akt1 in VSMCs During Atherogenesis
N Rotllan, AC Wanschel, A Fernandez-Hernando, AG Salerno, S Offermanns, WC Sessa, C Fernandez-Hernando |
Circulation research | 2015 |
MicroRNA-mediated mechanisms of the cellular stress response in atherosclerosis
A Schober, M Nazari-Jahantigh, C Weber |
Nature Reviews Cardiology | 2015 |
谷氧还蛋白在牙龈卟啉单胞菌脂多糖诱导脐静脉内皮细胞氧化应激中的作用
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2015 | |
Heme oxygenase-1 counteracts contrast media-induced endothelial cell dysfunction
CF Chang, XM Liu, KJ Peyton, W Durante |
Biochemical Pharmacology | 2014 |
Platelet-derived ERp57 mediates platelet incorporation into a growing thrombus by regulation of the αIIbβ3 integrin
L Wang, Y Wu, J Zhou, SS Ahmad, B Mutus, N Garbi, G Hämmerling, J Liu, DW Essex |
Blood | 2013 |
Sirolimus-FKBP12.6 Impairs Endothelial Barrier Function Through Protein Kinase C- Activation and Disruption of the p120-Vascular Endothelial Cadherin Interaction
A Habib, V Karmali, R Polavarapu, H Akahori, Q Cheng, K Pachura, FD Kolodgie, AV Finn |
Arteriosclerosis, thrombosis, and vascular biology | 2013 |
Oxidative stress improves coronary endothelial function through activation of the pro-survival kinase AMPK
Shafique E, Choy WC, Liu Y, Feng J, Cordeiro B, Lyra A, Arafah M, Yassin-Kassab A, Zanetti AV, Clements RT, Bianchi C, Benjamin LE, Sellke FW, Abid R |
Aging | 2013 |
Ablation of 3-phosphoinositide-dependent protein kinase 1 (PDK1) in vascular endothelial cells enhances insulin sensitivity by reducing visceral fat and suppressing angiogenesis
K Tawaramoto, K Kotani, M Hashiramoto, Y Kanda, T Nagare, H Sakaue, W Ogawa, N Emoto, M Yanagisawa, T Noda, M Kasuga, K Kaku |
Molecular Endocrinology | 2011 |
Animal, In Vitro, and Ex Vivo Models of Flow-Dependent Atherosclerosis: Role of Oxidative Stress
A Rezvan, CW Ni, N Alberts-Grill, H Jo |
Antioxidants & Redox Signaling | 2011 |
Myocardial AKT: the omnipresent nexus
MA Sussman, M Völkers, K Fischer, B Bailey, CT Cottage, S Din, N Gude, D Avitabile, R Alvarez, B Sundararaman, P Quijada, M Mason, MH Konstandin, A Malhowski, Z Cheng, M Khan, M McGregor |
Physiological reviews | 2011 |
Loss of Akt activity increases circulating soluble endoglin release in preeclampsia: identification of inter-dependency between Akt-1 and heme oxygenase-1
MJ Cudmore, S Ahmad, S Sissaoui, W Ramma, B Ma, T Fujisawa, B Al-Ani, K Wang, M Cai, F Crispi, PW Hewett, E Gratacós, S Egginton, A Ahmed |
European Heart Journal | 2011 |
Green Tea Polyphenol Epigallocatechin Gallate Reduces Endothelin-1 Expression and Secretion in Vascular Endothelial Cells: Roles for AMP-Activated Protein Kinase, Akt, and FOXO1
CE Reiter, J Kim, MJ Quon |
Endocrinology | 2010 |
Obesity increases vascular senescence and susceptibility to ischemic injury through chronic activation of Akt and mTOR
CY Wang, HH Kim, Y Hiroi, N Sawada, S Salomone, LE Benjamin, K Walsh, MA Moskowitz, JK Liao |
Science signaling | 2009 |
Smooth muscle Notch1 mediates neointimal formation after vascular injury
Y Li, K Takeshita, PY Liu, M Satoh, N Oyama, Y Mukai, MT Chin, L Krebs, MI Kotlikoff, F Radtke, T Gridley, JK Liao |
Circulation | 2009 |
The Akt1-eNOS Axis Illustrates the Specificity of Kinase-Substrate Relationships in Vivo
M Schleicher, J Yu, T Murata, B Derakhshan, D Atochin, L Qian, S Kashiwagi, AD Lorenzo, KD Harrison, PL Huang, WC Sessa |
Science signaling | 2009 |
Rho Kinase: An Important Mediator of Atherosclerosis and Vascular Disease
Zhou Q, Liao JK |
Current pharmaceutical design | 2009 |
ROCK1 Mediates Leukocyte Recruitment and Neointima Formation Following Vascular Injury
Kensuke Noma, Yoshiyuki Rikitake, Naotsugu Oyama, Guijun Yan, Pilar Alcaide, Ping-Yen Liu, Hongwei Wang, Daniella Ahl, Naoki Sawada, Ryuji Okamoto, Yukio Hiroi, Koichi Shimizu, Francis W. Luscinskas, Jianxin Sun, James K. Liao |
Journal of Clinical Investigation | 2008 |
Cyclophilin A mediates vascular remodeling by promoting inflammation and vascular smooth muscle cell proliferation
K Satoh, T Matoba, J Suzuki, MR O'Dell, P Nigro, Z Cui, A Mohan, S Pan, L Li, ZG Jin, C Yan, J Abe, BC Berk |
Circulation | 2008 |
Fine-tuning the angiogenic response to vascular endothelial growth factor
JK Liao |
Circulation research | 2008 |
HoxA5 stabilizes adherens junctions via increased Akt1
G Arderiu, I Cuevas, A Chen, M Carrio, L East, NJ Boudreau |
Cell adhesion & migration | 2007 |
Loss of Akt1 Leads to Severe Atherosclerosis and Occlusive Coronary Artery Disease
C Fernández-Hernando, E Ackah, J Yu, Y Suárez, T Murata, Y Iwakiri, J Prendergast, RQ Miao, MJ Birnbaum, WC Sessa |
Cell Metabolism | 2007 |
Requirement of Rac1 in the development of cardiac hypertrophy
M Satoh, H Ogita, K Takeshita, Y Mukai, DJ Kwiatkowski, JK Liao |
Proceedings of the National Academy of Sciences | 2006 |