Inhibition of Phosphatidylinositol 3-kinease suppresses formation and progression of experimental abdominal aortic aneurysms

Abstract

Accumulating evidence suggests an important role of Phosphatidylinositol 3-kinease (PI3K) pathway in inflammatory cells infiltration. Given the essential role of inflammatory cells infiltration during the formation and progression of abdominal aortic aneurysm (AAA), to investigate the possibility of preventing AAA formation and progression via targeting PI3K is anticipated. Here, experimental AAAs was created in rats by transient intraluminal porcine pancreatic elastase (PPE) infusion into the infrarenal aorta firstly. AAAs rats were administrated with vehicle or Wortmannin during the period of day 0 to day 28 after PPE infusion. The aortic diameter of rats treated with Wortmannin was significantly smaller than those treated with vehicle. Meanwhile, Elastin destruction score and SMC destruction score were significantly decreased in rats treated with Wortmannin. Furthermore, histological analysis revealed infiltration of inflammatory cells were significantly reduced in rats treated with Wortmannin. Finally, the mRNA expression of PI3K and protein expression of pAKT in human abdominal aneurismal aorta tissues was elevated as compare to normal aorta. Our study revealed that PI3K inhibitor suppresses experimental AAAs formation and progression, through mechanisms likely related to impairing inflammation cells infiltration and median elastin degradation. These findings indicated that PI3K inhibitor may hold substantial translation value for AAA diseases.

Low glucose and serum levels cause an increased inflammatory factor in 3T3-L1 cell through Akt, MAPKs and NF-кB activation

“…NF-кB is closely associated with the regulation of inflammation and immune responses in the physiological or pathophysiological processes of AAA [ 29 ]. Several stimuli, such as angiotensin II, ROS, and MMP-9, activate NF-κB signalling in AAA diseases [ 30–32 ].…”

“…Recently, Akt signalling was reported to be increased during AAA development, and suppression of Akt inhibited AAA formation [ 29 ]. Our results showed that upon returning to normal nutrient medium, 3T3-L1 adipocyte-differentiated cells significantly suppressed the glucose- and serum deprivation-induced increase in phosphorylated-Akt expression.…”

An Overview of ADAM9: Structure, Activation, and Regulation in Human Diseases

“…ADAM9, modulated by miR-126, could induce inflammatory cascades and the infiltration of macrophages into the aortic wall [ 20 ]. Additionally, knockdown of ADAM9 suppressed aneurysm formation through PI3K/AKT/NF-κB pathway inhibition, an activated pathway in the murine aneurysm model [ 67 ]. Therefore, ADAM9 can induce retinal disorders as well as pathological vascular diseases.…”

LncRNA SENCR suppresses abdominal aortic aneurysm formation by inhibiting smooth muscle cells apoptosis and extracellular matrix degradation

“…Numerous animal models, such as angiotensin II (Ang-II)-induced AAA mouse model, were developed to explore more treatment methods for the disease [ 6 - 8 ]. Several lines of evidence have revealed that the number of smooth muscle cells (SMCs) in AAA tissues is significantly reduced, and the pathogenesis of AAA is closely associated with inflammation in the aortic wall and extracellular matrix degeneration [ 9 , 10 ]. Hence, it is necessary to investigate the pathological mechanism of AAA and find new molecular targets for AAA treatment.…”