Mobilization of fatty acids by endothelial phospholipase prevents aortic dissection

Aortic dissection involves the separation of the aortic wall layers and it is caused by bleeding within the aortic wall or a tear in aorta’s intimal layer. It is a life-threatening condition whose major pathologic feature is the fragility of the medial wall of the aorta. However, the underlying mechanisms of this condition are not fully understood. Phospholipase A₂ (PLA₂) enzymes cause the spatiotemporal release of unsaturated fatty acids from membrane phospholipids. Secreted PLA₂ (sPLA₂) family is the largest subgroup of PLA₂ enzymes identified to date and they have been implicated in cardiovascular diseases. There is conflicting evidence that suggest the possibility of some sPLA₂s having a protective instead of a detrimental role in vascular diseases. No known study has investigated the role of sPLA₂s in aortic dissection.

In a new study, Kazuhiro Watanabe, Kiyotaka Kugiyama, from the University of Yamanashi together with Yoshitaka Taketomi and Yoshimi Miki and led by Professor Makoto Murakami from the University of Tokyo, they sought to identify the role of sPLA2s in aortic dissection. Their findings show that the activity of group V sPLA₂ (sPLA₂-V) protects against aortic dissection. The study is published in the Journal of Biological Chemistry.

The research team conducted a quantitative RT-PCR which showed that several sPLA₂s (Pla2g2d, Pla2g2e, Pla2g3, and Pla2g5) were significantly expressed in the aorta of the study mice, but, Pla2g5 (encoding sPLA₂-V) showed the highest expression. The expression level of Pla2g5 in the aorta was found to be almost equivalent to that in the heart, which has been established to express this sPLA₂ most extensively. Pla2g5 expression levels in anatomically distinct aortas were almost equal whereas its expression level in the inferior vena cava was less than half of that in the aortas. The team observed that the localization of the sPLA₂-V protein was predominantly in the endothelial cell (EC) lining of the aorta and in the myocardium in Pla2g5^+/+ mice, but its staining was absent in Pla2g5^-/- mice.

sPLA₂-V was found to be the major sPLA₂ expressed in aortic ECs in mice. The infusion of AT-II into mice resulted in a decrease in the aortic expression of Pla2g5 mRNA as well as mRNAs for the other three sPLA₂s over 24–48h. Even at a young age (8–12 weeks old), global or endothelial-specific Pla2g5^-/- mice that were exposed to AT-II for a shorter period were noticed to have frequently developed aortic dissection. After 7 days exposure to AT-II infusion, up to half of the Pla2g5^-/- mice developed aortic dissection, and it mainly occurred in the thoracic ascending aorta, many times with extension to the aortic arch.

A significant elevation of oleic acid and linoleic acid was observed in the aorta of Pla2g5^+/+ mice after AT-II challenge, whereas in that of Pla2g5^-/- mice, the elevation of these unsaturated fatty acids was minimal. Oleic acid and linoleic acid released from Pla2g5 from endothelial cells caused an up-regulation in the expression of lysyl oxidase (LOX), an enzyme that crosslinks extracellular matrix, in vascular smooth muscle cells, thereby stabilizing the aortic wall. The increased susceptibility of Pla2g5^-/- mice to aortic dissection was noticed to be rescued by oleic acid- and linoleic acid-rich diet.

Through the study, the researchers successfully demonstrated the presence of a functional link between aortic stabilization and phospholipid metabolism. This will be useful in developing new strategies for the diagnosis and treatment of aortic dissection. Furthermore, the study provides pave the way for future studies to identify the possible benefits of oleic acid-rich diet (such as olive oil-supplemented Mediterranean diet) to cardiovascular health.