| First Author | Aravani D | Year | 2019 |
| Journal | Circulation | Volume | 140 |
| Issue | 6 | Pages | 500-513 |
| PubMed ID | 31163988 | Mgi Jnum | J:280707 |
| Mgi Id | MGI:6369484 | Doi | 10.1161/CIRCULATIONAHA.119.041059 |
| Citation | Aravani D, et al. (2019) HHIPL1, a Gene at the 14q32 Coronary Artery Disease Locus, Positively Regulates Hedgehog Signaling and Promotes Atherosclerosis. Circulation 140(6):500-513 |
| abstractText | BACKGROUND: Genome-wide association studies have identified chromosome 14q32 as a locus for coronary artery disease. The disease-associated variants fall in a hitherto uncharacterized gene called HHIPL1 (hedgehog interacting protein-like 1), which encodes a sequence homolog of an antagonist of hedgehog signaling. The function of HHIPL1 and its role in atherosclerosis are unknown. METHODS: HHIPL1 cellular localization, interaction with sonic hedgehog (SHH), and influence on hedgehog signaling were tested. HHIPL1 expression was measured in coronary artery disease-relevant human cells, and protein localization was assessed in wild-type and Apoe(-/-) (apolipoprotein E deficient) mice. Human aortic smooth muscle cell phenotypes and hedgehog signaling were investigated after gene knockdown. Hhipl1(-/-) mice were generated and aortic smooth muscle cells collected for phenotypic analysis and assessment of hedgehog signaling activity. Hhipl1(-/-) mice were bred onto both the Apoe(-/-) and Ldlr(-/-) (low-density lipoprotein receptor deficient) knockout strains, and the extent of atherosclerosis was quantified after 12 weeks of high-fat diet. Cellular composition and collagen content of aortic plaques were assessed by immunohistochemistry. RESULTS: In vitro analyses revealed that HHIPL1 is a secreted protein that interacts with SHH and increases hedgehog signaling activity. HHIPL1 expression was detected in human smooth muscle cells and in smooth muscle within atherosclerotic plaques of Apoe(-/-) mice. The expression of Hhipl1 increased with disease progression in aortic roots of Apoe(-/-) mice. Proliferation and migration were reduced in Hhipl1 knockout mouse and HHIPL1 knockdown aortic smooth muscle cells, and hedgehog signaling was decreased in HHIPL1-deficient cells. Hhipl1 knockout caused a reduction of >50% in atherosclerosis burden on both Apoe(-/-) and Ldlr(-/-) knockout backgrounds, and lesions were characterized by reduced smooth muscle cell content. CONCLUSIONS: HHIPL1 is a secreted proatherogenic protein that enhances hedgehog signaling and regulates smooth muscle cell proliferation and migration. Inhibition of HHIPL1 protein function might offer a novel therapeutic strategy for coronary artery disease. |
