Development - Angiotensin activation of Akt

Angiotensin's activation of Akt via transactivation EGFR

Angiotensin II, a major effector peptide of the renin-angiotensin system, is now believed to play a critical role in the pathogenesis of cardiovascular remodeling associated with hypertension, heart failure, and atherosclerosis [1].

Angiotensin II receptor type1 mediates the major cardiovascular effects of angiotensin-II. It relate to guanine nucleotide-binding regulatory protein (G protein)-coupled receptor (GPCR) superfamily [2]. The human angiotensin II receptor type1 is found in liver, lung, adrenal, and adrenocortical adenomas, but not in pheochromocytomas [3].

It has been shown that angiotensin II may stimulate a serine/threonine protein kinase (Akt) through activate of p38 mitogen-activated protein kinase (p38 MAPK) and transactivation of epidermal growth factor receptor (EGFR) in vascular smooth muscle cells [4].

Upon binding with angiotensin II, the angiotensin II receptor type1 is stabilized in its active conformation and stimulates heterotrimeric G proteins (most notably G q/11). These Gq/11-proteins dissociate into alpha (G alpha q/11) and beta/gamma (G beta/gamma) subunits [5]. Both subunits take part in this pathway activation Akt.

G alpha q/11 and G beta/gamma act as signal transducers for activation of phospholipase C beta (PLC-beta) [6]. PLC-beta activation leads to hydrolysis of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and the generation of diacylglycerol (DAG) and inositol trisphosphate (IP3) [7]. DAG and IP3 stimulate protein kinase C, type alpha (PKC-alpha) and mobilise intracellular Ca²⁺, respectively. These effectors are thought to mediate most of the well-established acute responses to angiotensin II, including vasoconstriction, aldosterone biosynthesis and thirst/salt appetite [8].

PI(4,5)P2, Ca²⁺/calmodulin-dependent protein kinase II (CaMK II) and (PKC-alpha), may activate of cytosolic phospholipase A2, group-IVA (PLA2G4A) [9], [10], [11], [12].

PLA2G4A hydrolyzes phosphatidylcholine (2-arachidonoyl-1-alkyl-sn-glycero-3-phosphocholine) to produce lyso-phosphatidylcholine and arachidonic acid [13], [14], [15].

Further, arachidonic acid is metabolized by some enzymes into hydroxyeicosatetraenoic and/or epoxyeicosatrienoic acids, which may activated p38 MAPK. For example, 12-lipoxygenase (ALOX12) converts arachidonic acid to 12-hydroperoxyeicosatetraenoic acid (12-HPETE) which than converts to 12-hydroxyeicosatetraenoic acid (12-HETE) by glutathione peroxidase 1 (GPX1) and peroxiredoxin 6 (NSGPeroxidase).

It has been shown that 12-HETE activates small GTP binding proteins: cell division cycle 42 (Cdc42) and ras-related C3 botulinum toxin substrate 1 (Rac1) [16], [17] and stimulates mitogen-activated protein kinase kinase kinase 11 (MLK3)/ dual specificity mitogen activated protein kinase kinases (MEK3 and MEK6)/ p38 MAPK pathway [4], [18].

Isoforms p38 MAPKs (alpha, beta, gamma, delta) activate phospholipase D2 (PLD2) and results in 1-acyl-2-arachidonoyl-glycerophosphate production, which stimulates EGFR transactivation [4].

Transactivated EGFR in turn allows to activate phosphatidylinositol 3-kinase (PI3K), which stimulates the conversion of PI(4,5)P2 to phosphatidylinositol (3,4,5) trisphosphate (PI(3,4,5)P3).

PI(3,4,5)P3 binds to the pleckstrin-homology domain of Akt, recruits Akt to the plasma membrane, and exposes Akt to phosphorylation at by 3-phosphoinositide-dependent protein kinase 1 (PDK) [19].

Phosphorylated and activated Akts stimulates several downstream effectors, which regulate cell survival, cell cycle, glucose metabolism, angiogenesis, vasomotor tone, and protein synthesis [20].

References:

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