The critical role of Akt in cardiovascular function

Abstract

Akt kinase, a member of AGC kinases, is important in many cellular functions including proliferation, migration, cell growth and metabolism. There are three known Akt isoforms which play critical and diverse roles in the cardiovascular system. Akt activity is regulated by its upstream regulatory pathways at transcriptional and post-translational levels. beta-catenin/Tcf-4, GLI1 and Stat-3 are some of few known transcriptional regulators of AKT gene. Threonine 308 and serine 473 are the two critical phosphorylation sites of Akt1. Translocation of Akt to the cell membrane facilitates PDK1 phosphorylation of the threonine site. The serine site is phosphorylated by mTORC2. Ack1, Src, PTK6, TBK1, IKBKE and IKKε are some of the non-canonical pathways which affect the Akt activity. Protein-protein interactions of Akt to actin and Hsp90 increase the Akt activity while Akt binding to other proteins such as CTMP and TRB3 reduces the Akt activity. The action of Akt on its downstream targets determines its function in cardiovascular processes such as cell survival, growth, proliferation, angiogenesis, vasorelaxation, and cell metabolism. Akt promotes cell survival via caspase-9, YAP, Bcl-2, and Bcl-x activities. Inhibition of FoxO proteins by Akt also increases cell survival by transcriptional mechanisms. Akt stimulates cell growth and proliferation through mTORC1. Akt also increases VEGF secretion and mediates eNOS phosphorylation, vasorelaxation and angiogenesis. Akt can increase cellular metabolism through its downstream targets GSK3 and GLUT4. The alterations of Akt signaling play an important role in many cardiovascular pathological processes such as atherosclerosis, cardiac hypertrophy, and vascular remodeling. Several Akt inhibitors have been developed and tested as anti-tumor agents. They could be potential novel therapeutics for the cardiovascular diseases.

Astragaloside IV Improves Vasodilatation Function by Regulating the PI3K/Akt/eNOS Signaling Pathway in Rat Aorta Endothelial Cells

“…The PI3K and serine/threonine protein kinase Akt are the critical upstream regulators to activate eNOS [39]. Akt is activated in response to PI3K and its lipid products phosphatidylinositol 3, 4, 5-trisphosphate (Ptdlns [3,4,5]P3, PIP 3 ) and Ptdlns(3,4) P 2 (PIP 2 ) [40].…”

C‐C Motif Chemokine Receptor 9 Exacerbates Pressure Overload–Induced Cardiac Hypertrophy and Dysfunction

“…Although numerous studies have revealed crucial proteins and pathways involved in the process of cardiac hypertrophy, including the mitogen‐activated protein kinase (MAPK)3 and phosphatidylinositol 3 kinase–AKT–mammalian target of rapamycin (mTOR)4, 5, 6 signaling pathways, the underlying mechanism of cardiac hypertrophy remains elusive. Recently, numerous studies have reported the effects of immunologic molecules in cardiac hypertrophy 7, 8, 9.…”

MicroRNA-142-3p Induces Atherosclerosis-Associated Endothelial Cell Apoptosis by Directly Targeting Rictor

“…Rictor is necessary for Akt phosphorylation on Ser473 and that a reduction in Rictor expression inhibits an Akt effector [34]. Upon activation Akt mediates pro-survival and anti-apoptosis in part via phosphorylating downstream target proteins including eNOS, BAD, Caspase-9, Fox1, Fox3a, YAP and MDM2 [35]. Among these target proteins, one of the most important one is eNOS.…”