Phospholipase C epsilon insufficiency causes ascending aortic aneurysm and dissection

American journal of physiology. Heart and circulatory physiology(2022)

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摘要
Phospholipase C epsilon (PLC epsilon) is a phospholipase C isoform with a wide range of physiological functions. It has been implicated in aortic valve disorders, but its role in frequently associated aortic disease remains unclear. To determine the role of PLCe in thoracic aortic aneurysm and dissection (TAAD) we used PLC epsilon-deficient mice, which develop aortic valve insufficiency and exhibit aortic dilation of the ascending thoracic aorta and arch without histopathological evidence of injury. Fourteen days of infusion of Plce1(+/+) and Plce1(-/-) mice with angiotensin II (ANG II), which induces aortic dilation and dissection, led to sudden death secondary to ascending aortic dissection in 43% of Plce1(-/-) versus 5% of Plce1(+/+) mice (P < 0.05). Medial degeneration and TAAD were detected in 80% of Plce1(-/-) compared with 10% of Plce1(+/+) mice (P < 0.05) after 4 days of ANG II. Treatment with ANG II markedly increased PLC epsilon expression within the ascending aortic adventitia. Total RNA sequencing demonstrated marked upregulation of inflammatory and fibrotic pathways mediated by interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha. In silico analysis of whole exome sequences of 258 patients with type A dissection identified 5 patients with nonsynonymous PLCE1 variants. Our data suggest that PLC epsilon deficiency plays a role in the development of TAAD and aortic insufficiency. NEW & NOTEWORTHY We describe a novel phenotype by which PLC epsilon deficiency predisposes to aortic valve insufficiency and ascending aortic aneurysm, dissection, and sudden death in the setting of ANG II-mediated hypertension. We demonstrate PLCE1 variants in patients with type A aortic dissection and aortic insufficiency, suggesting that PLCE1 may also play a role in human aortic disease. This finding is of very high significance because it has not been previously demonstrated that PLC epsilon directly mediates aortic dissection.
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关键词
angiotensin II,aortic dissection,aortic insufficiency,signaling pathway analysis
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