Dataset Information

Inhibition of ROR?/? suppresses atherosclerosis via inhibition of both cholesterol absorption and inflammation.

ABSTRACT:

Objective

Cardiovascular diseases (CVDs) are the leading cause of mortality in Western countries. Atherosclerosis is a multi-step inflammatory disease characterized at early stages by accumulation of cholesterol in the arterial wall followed by recruitment of immune cells. We sought to determine if pharmacological suppression of ROR?/? activity is beneficial in treatment of atherosclerosis.

Methods

To identify the role of ROR? and ROR? in atherosclerosis, we used the LDL-R(-/-) mouse model of atherosclerosis placed on a high cholesterol diet treated with SR1001, a ROR?/? inverse agonist, for four weeks.

Results

Our results demonstrate that treatment with the ROR inverse agonist substantially decreases plaque formation in vivo. The mechanism of the anti-atherogenic activity of the inhibition of ROR?/? activity appeared to be due to targeting two distinct pathways. SR1001 treatment reduced plasma low density lipoprotein (LDL) level without affecting high density lipoprotein (HDL) via increasing intestinal cholesterol excretion. Treatment with SR1001 also induced an anti-atherogenic immune profile that was characterized by a reduction in Th17 cells and an increase in Treg and Th2 cells. Our data suggest that ROR? and ROR? play a critical role in atherosclerosis development by regulating at least two major pathways important in the pathology of this disease: cholesterol flux and inflammation.

Conclusion

Our data suggest that pharmacological targeting of ROR?/? may be an effective method for treatment of atherosclerosis offering a distinct mechanism of action relative to statins.

SUBMITTER: Billon C

PROVIDER: S-EPMC5034492 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Publications

Inhibition of RORα/γ suppresses atherosclerosis via inhibition of both cholesterol absorption and inflammation.

Billon Cyrielle C Sitaula Sadichha S Burris Thomas P TP

Molecular metabolism 20160725 10

<h4>Objective</h4>Cardiovascular diseases (CVDs) are the leading cause of mortality in Western countries. Atherosclerosis is a multi-step inflammatory disease characterized at early stages by accumulation of cholesterol in the arterial wall followed by recruitment of immune cells. We sought to determine if pharmacological suppression of RORα/γ activity is beneficial in treatment of atherosclerosis.<h4>Methods</h4>To identify the role of RORα and RORγ in atherosclerosis, we used the LDL-R(-/-) mo ...[more]

PMID: 27689012

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