Downregulation of Cavin‐1 Expression via Increasing Caveolin‐1 Degradation Prompts the Proliferation and Migration of Vascular Smooth Muscle Cells in Balloon Injury–Induced Neointimal Hyperplasia

Abstract

BackgroundPercutaneous coronary intervention has been widely used in the treatment of ischemic heart disease, but vascular restenosis is a main limitation of percutaneous coronary intervention. Our previous work reported that caveolin‐1 had a key functional role in intimal hyperplasia, whereas whether Cavin‐1 (another important caveolae‐related protein) was involved is still unknown. Therefore, we will investigate the effect of Cavin‐1 on neointimal formation.Methods and ResultsBalloon injury markedly reduced Cavin‐1 protein and enhanced ubiquitin protein expression accompanied with neointimal hyperplasia in injured carotid arteries, whereas Cavin‐1 mRNA had no change. In cultured vascular smooth muscle cells (VSMCs), Cavin‐1 was downregulated after inhibition of protein synthesis by cycloheximide, which was distinctly prevented by pretreatment with proteasome inhibitor MG132 but not by lysosomal inhibitor chloroquine, suggesting that proteasomal degradation resulted in Cavin‐1 downregulation. Knockdown of Cavin‐1 by local injection of Cavin‐1 short hairpin RNA (shRNA) into balloon‐injured carotid arteries in vivo promoted neointimal formation. In addition, inhibition or overexpression of Cavin‐1 in cultured VSMCs in vitro prompted or suppressed VSMC proliferation and migration via increasing or decreasing extracellular signal‐regulated kinase phosphorylation and matrix‐degrading metalloproteinases‐9 activity, respectively. However, under basic conditions, the effect of Cavin‐1 on VSMC migration was stronger than on proliferation. Moreover, our results indicated that Cavin‐1 regulated caveolin‐1 expression via lysosomal degradation pathway.ConclusionsOur study revealed the role and the mechanisms of Cavin‐1 downregulation in neointimal formation by promoting VSMC proliferation, migration, and synchronously enhancing caveolin‐1 lysosomal degradation. Cavin‐1 may be a potential therapeutic target for the treatment of postinjury vascular remodeling.

Caveolin as a Novel Potential Therapeutic Target in Cardiac and Vascular Diseases: A Mini Review

“…However, other studies revealed different roles of caveolin in regulating the remodeling of vascular smooth muscle. Zhou et al [29] found that the knockdown of cavin-1 via the local injection of short hairpin RNA into balloon-injured carotid arteries in vivo promotes neointimal formation. Additionally, the inhibition of caveolin-1 in cultured vascular smooth muscle cells in vitro was found to promote the proliferation and migration of smooth muscle cells by increasing extracellular signalregulated kinase phosphorylation and matrix-degrading metalloproteinase-9 (MMP9) activity.…”

Caveolin‑1 modulates hypertensive vascular remodeling via regulation of the Notch pathway

“…in addition, cav-1 participated in the regulation of vascular remodeling. The upregulation of cav-1 decreased cavin-1 expression and promoted the viability and migration of vascular smooth muscle cells (VSMcs) in balloon injury-induced neointimal hyperplasia (23). it was also found that cav-1 deficiency prevented ang ii-mediated hypertrophy and inward remodeling of pial arterioles, which indicated that cav-1 promoted ang-ii-mediated hypertrophy and vascular remodeling (24).…”

Endothelial Dysfunction and Disruption in Pulmonary Hypertension

“…In a carotid artery-injury model, the local loss of cavin-1 is reported to promote neointima formation. Furthermore, in cultured vascular SMC, the overexpression of cavin-1 suppresses SMC proliferation and migration, whereas its inhibition promotes cell proliferation and migration [71]. Cavin-1 knockout mice display lung pathological changes such as remodeled pulmonary vessels, PH and right ventricular hypertrophy.…”