Targeting feed-forward signaling of TGFβ/NOX4/DHFR/eNOS uncoupling/TGFβ axis with anti-TGFβ and folic acid attenuates formation of aortic aneurysms: Novel mechanisms and therapeutics.

ABSTRACT: In the present study we aimed to identify novel mechanisms and therapeutics for thoracic aortic aneurysm (TAA) in Fbn1^C1039G/+ Marfan Syndrome (MFS) mice. The expression of mature/active TGFβ and its downstream effector NOX4 were upregulated while tetrahydrobiopterin (H₄B) salvage enzyme dihydrofolate reductase (DHFR) was downregulated in Fbn1^C1039G/+ mice. In vivo treatment with anti-TGFβ completely attenuated NOX4 expression, restored DHFR protein abundance, reduced ROS production, recoupled eNOS and attenuated aneurysm formation. Intriguingly, oral administration with folic acid (FA) to recouple eNOS markedly alleviated expansion of aortic roots and abdominal aortas in Fbn1^C1039G/+ mice, which was attributed to substantially upregulated DHFR e

SUBMITTER: Huang K 

PROVIDER: S-EPMC7585948 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature