Acetate and Endothelial Pathobiology

Chronic vascular inflammation is a hallmark of atherosclerosis, pulmonary arterial
hypertension (PAH) and related conditions. It is also one of the principal causes of endothelial-
to-mesenchymal transition (EndMT). We have recently demonstrated that disruption of EndMT,
achieved by inhibiting endothelial-specific TGFβ signaling input, results in extensive (~70%)
regression of established atherosclerotic lesion and prevention of development of new ones. It
also prevents development of hypoxia-induced PAH. These data suggest that EndMT is key to
the development and progression of illnesses associated with chronic inflammation, such as
atherosclerosis, PAH, and transplant arteriopathy.
However, a therapeutic strategy that relies on suppressing EndMT via control of endothelial
TGFβ signaling is complicated because of the need of endothelial-specific delivery of
therapeutic agents (systemic inhibition of TGFβ signaling is fraught with side effects and has
been shown to promote atherosclerosis via its effects on smooth muscle cells). For these
reasons, we focused on identifying another EndMT control point that can serve as an effective
therapeutic target. Since endothelial cells have unique metabolic requirements and pathways,
we concentrated on identifying potential metabolic-related control of EndMT.
Our preliminary studies indicate that there indeed is metabolic control of EndMT that
operates via acetylation-dependent regulation of TGFβ signaling. Moreover, the Ac-CoA needed
for these acetylation events appears to be in large part derived atypically from acetate. Our goal
in this application is to rigorously define and characterize the unique endothelial metabolic
pathway that leads to generation of cytoplasmic Ac-CoA from acetate and the role that this Ac-
CoA plays in TGFβ signaling. This will be tested in vitro and in vivo using genetically engineered
mice. Finally, we will test two distinct translational strategies – a nanoparticle-based EC-specific
RNAi delivery, and an oral specific inhibitor to test the effect of suppression of acetate-based
Ac-CoA production on the development and progression of atherosclerosis

Grant Number: 5R01HL167014-03
NIH Institute/Center: NIH
Principal Investigator: Zoltan Arany