Project Summary/Abstract
Coronary heart disease (CHD) is the single leading cause of death in the United States. Coronary
revascularization, including coronary artery bypass graft and percutaneous coronary intervention, is the most
common modality in patients with CHD. However, it is often associated with a high incidence of restenosis.
Although the rate of restenosis is reduced significantly by using bare-metal stent (BMS) and particularly with
drug-eluting stent (DES), a persistently high rate of restenosis after BMS and an increased risk of in-stent
thrombosis with DES has been encountered as a major significant gap in the field. The current application
proposes to bridge this gap and specifically investigates the role of the smooth muscle cell (SMC) BMAL1 in
neointimal hyperplasia in mouse models of arterial injury. BMAL1 is a core molecular component of the
circadian clock. It has long been believed that loss of function of BMAL1 is detrimental to well-being. However,
this dogma was challenged by our recent report that genetic deletion of Bmal1 in SMCs (SM-Bmal1-KO)
protects mice from aldosterone or angiotensin II-induced abdominal aortic aneurysm. Consistent with this
finding, our preliminary demonstrate that SMC-specific Bmal1 deletion also protects mice femoral artery wire
injury- or carotid artery ligation-induced neointimal hyperplasia. While the underlying mechanism remains
elusive, our preliminary data reveal arachidonic acid metabolism is most significantly affected by SMC-specific
Bmal1 deletion. Interestingly, among enzymes implicated in arachidonic acid metabolism, cytosolic
phospholipase A2 alpha (cPLA2¿) is most downregulated by SMC-specific Bmal1 deletion. Mechanistically, our
preliminary data illustrate that BMAL1 binds to the mouse cPLA2¿ promoter, and SMC BMAL1 is required for
vascular injury-induced cPLA2¿ upregulation in neointima. Given the potential role of cPLA2¿ in VSMC
proliferation and neointimal hyperplasia, we hypothesize that upregulation of BMAL1 in SMCs by vascular
injury promotes cPLA2¿ expression, thus mediating the initiation and progression of neointimal hyperplasia and
significantly contributing to the development of restenosis after coronary revascularization. Aim 1 will test the
hypothesis that upregulation of SMC BMAL1 by vascular injury is critical for the onset and progression of
neointimal hyperplasia. Aim 2 will define the mechanism by which SMC BMAL1 regulates cPLA2¿ and thereby
mediates vascular injury-induced neointimal hyperplasia. To achieve the goals, SM-Bmal1-KO, SM-cPLA2¿-
KO, and SM-Bmal1/cPLA2¿-KO mice will be subjected to femoral artery wire injury or carotid artery ligation to
induce neointimal hyperplasia and to determine the mechanism by which SMC BMAL1 and cPLA2¿ mediate
vascular injury-induced neointimal hyperplasia. Results from the proposed studies will provide new mechanistic
insight on how SMC BMAL1 mediates vascular injury-induced neointimal hyperplasia via cPLA2¿. Moreover,
results from the proposed studies will provide preclinical evidence that inhibiting the BMAL1/cPLA2¿ signaling
at the lesion site is a new therapeutic strategy against restenosis after coronary revascularization.