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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.

SUBMITTER: Yu J

PROVIDER: S-EPMC5680315 | biostudies-other | 2017 Nov

REPOSITORIES: biostudies-other

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

Yu Jing J Liu Rui R Huang Jianhua J Wang Lixin L Wang Wei W

Scientific reports 20171109 1

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 ...[more]

PMID: 29123158

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Project description:ObjectiveAngiotensin (Ang) II type 1 receptor (AT1) activation is essential for the development of exogenous Ang II-induced abdominal aortic aneurysms (AAAs) in hyperlipidemic animals. Experimental data derived from this modeling system, however, provide limited insight into the role of endogenous Ang II in aneurysm pathogenesis. Consequently, the potential translational value of AT1 inhibition in clinical AAA disease management remains incompletely understood on the basis of the existing literature.MethodsAAAs were created in wild-type (WT) and AT1a knockout (KO) mice by intra-aortic infusion of porcine pancreatic elastase (PPE). WT mice were treated with the AT1 receptor antagonist telmisartan, 10 mg/kg/d in chow, or the peroxisome proliferator-activated receptor γ (PPARγ) antagonist GW9662, 3 mg/kg/d through oral gavage, beginning 1 week before or 3 days after PPE infusion. Influences on aneurysm progression as well as mechanistic insights into AT1-mediated pathogenic processes were determined using noninvasive ultrasound imaging, histopathology, aortic gene expression profiling, and flow cytometric analysis.ResultsAfter PPE infusion, aortic enlargement was almost completely abrogated in AT1a KO mice compared with WT mice. As defined by a ≥50% increase in aortic diameter, no PPE-infused, AT1a KO mouse actually developed an AAA. On histologic evaluation, medial smooth muscle cellularity and elastic lamellae were preserved in AT1a KO mice compared with WT mice, with marked attenuation of mural angiogenesis and leukocyte infiltration. In WT mice, telmisartan administration effectively suppressed aneurysm pathogenesis after PPE infusion as well, regardless of whether treatment was initiated before or after aneurysm creation or continued for a limited or extended time. Telmisartan treatment was associated with reduced messenger RNA levels for CCL5 and matrix metalloproteinases 2 and 9 in aneurysmal aortae, with no apparent effect on PPARγ-regulated gene expression. Administration of the PPARγ antagonist GW9662 failed to "rescue" the aneurysm phenotype in telmisartan-treated, PPE-infused WT mice. Neither effector T-cell differentiation nor regulatory T-cell cellularity was affected by telmisartan treatment status.ConclusionsTelmisartan effectively suppresses the progression of elastase-induced AAAs without apparent effect on PPARγ activation or T-cell differentiation. These findings reinforce the critical importance of endogenous AT1 activation in experimental AAA pathogenesis and reinforce the translational potential of AT1 inhibition in medical aneurysm disease management.

Dataset Information

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

Publications

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

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