Atchison DK, O'Connor CL, Converso-Baran K, Bergin IL, Zhang H, Wang Y, Hartman JR, Ju W, Smrcka AV, Ganesh SK, and Bitzer M. Phospholipase Cε Insufficiency Causes Ascending Aortic Aneurysm and Dissection. Am J Physiol Heart Circ Physiol 2022.
American journal of physiology. Heart and circulatory physiology
Phospholipase Cε (PLCε) is a phospholipase C isoform with a wide range of physiologic functions. It has been implicated in aortic valve disorders but its role in frequently associated aortic disease remains unclear. To determine the role of PLCε in thoracic aortic aneurysm and dissection (TAAD) we used PLCε deficient mice which develop aortic valve insufficiency and also 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, lead 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 to 10% of Plce1(+/+) mice (p<0.05) after four days of Ang II. Treatment with Ang II markedly increased PLCε expression within the ascending aortic adventitia. RNA sequencing of ascending aorta tissue prior to aortic rupture demonstrated marked increased expression of pro-inflammatory and fibrotic signaling pathways, as well as upstream regulators interleukin-1β, interleukin-6, and tumor necrosis factor-α in Plce1(-/-) mice. In silico analysis of whole-exome sequences of 258 patients with Type A dissection identified 5 patients with non-synonymous PLCE1 variants. Our data suggest PLCε as a novel regulator in the development of TAAD and aortic insufficiency.
Medical Subject Headings
Humans; Mice; Animals; Aortic Valve Insufficiency; Aneurysm, Ascending Aorta; Mice, Inbred C57BL; Aortic Aneurysm; Aortic Dissection; Angiotensin II; Hypertension; Death, Sudden; Aortic Aneurysm, Thoracic
ePub ahead of print