The CCL5/CCR5 Axis Promotes Vascular Smooth Muscle Cell Proliferation and Atherogenic Phenotype Switching

Abstract

Background/Aims: Hyperlipidemia induces dysfunction in the smooth muscle cells (SMCs) of the blood vessels, and the vascular remodeling that ensues is a key proatherogenic factor contributing to cardiovascular events. Chemokines and chemokine receptors play crucial roles in vascular remodeling. Here, we examined whether the hyperlipidemia-derived chemokine CCL5 and its receptor CCR5 influence vascular SMC proliferation, phenotypic switching, and explored the underlying mechanisms. Methods: Thoracoabdominal aorta were isolated from wild-type, CCL5 and CCR5 double-knockout mice (CCL5^–/–CCR5^–/–) fed a high-fat diet (HFD) for 12 weeks. Expression of the contractile, synthetic, and proliferation markers were assayed using immunohistochemical and western blotting. The effects of CCL5 and palmitic acid on cultured SMC proliferation and phenotypic modulation were evaluated using flow cytometry, bromodeoxyuridine (BrdU), and western blotting. Results: Wild-type mice fed an HFD showed markedly increased total cholesterol, triglyceride, and CCL5 serum levels, as well as significantly increased CCL5 and CCR5 expression in the thoracoabdominal aorta vs. normal-diet-fed controls. HFD-fed CCL5^-/-CCR5^-/- mice showed significantly decreased expression of the synthetic phenotype marker osteopontin and the proliferation marker proliferating cell nuclear antigen, and increased expression of the contractile phenotype marker smooth muscle α-actin in the thoracoabdominal aorta vs. wild-type HFD-fed mice. Human aorta-derived SMCs stimulated with palmitic acid showed significantly increased expression of CCL5, CCR5, and synthetic phenotype markers, as well as increased proliferation. CCL5-treated SMCs showed increased cell cycle regulatory protein expression, paralleling increased synthetic and decreased contractile phenotype marker expression. Inhibition of CCR5 activity by the specific antagonist maraviroc or its expression using small interfering RNA significantly inhibited human aortic SMC proliferation and synthetic phenotype formation. Therefore, CCL5 induces SMC proliferation and phenotypic switching from a contractile to synthetic phenotype via CCR5. CCL5-mediated SMC stimulation activated ERK1/2, Akt/p70S6K, p38 MAPK, and NF-κB signaling. NF-κB inhibition significantly reduced CCR5 expression along with CCR5-induced SMC proliferation and synthetic phenotype formation. Conclusions: Hyperlipidemia-induced CCL5/CCR5 axis activation serves as a pivotal mediator of vascular remodeling, indicating that CCL5 and CCR5 are key chemokine-related factors in atherogenesis. SMC proliferation and synthetic phenotype transformation attenuation by CCR5 pharmacological inhibition may offer a new approach to treatment or prevention of atherosclerotic diseases associated with hyperlipidemia.

Chemokine Receptor 5, a Double-Edged Sword in Metabolic Syndrome and Cardiovascular Disease

“…CCL5 is pro-angiogenic in the ischemic tissues and subcutaneous model, promotes the revascularization and muscle regeneration by binding to its receptor, CCR5. Suffee et al, 2012;Liu et al, 2014;Zhang et al, 2015b;Ridiandries et al, 2016;Lin et al, 2018. CCR5 Monocytes/macrophages, activated T cells, endothelial cells, endothelial progenitor cells (EPCs), natural killer cells, astrocytes, microglia, and neurons.…”

“…In HFD fed mouse model, the CCR5 and CCL5 gene knockouts showed significantly decreased levels of serum lipids and increased expressions of the SMCs contractile phenotype in the thoracoabdominal aorta as compared with the levels observed in wild-type mice. In vitro, CCL5 treated human aorta derived SMCs could induce cell proliferation and promote the phenotypic switching from the contractile to the synthetic phenotype (Lin et al, 2018).…”

Nonalcoholic Fatty Liver Disease

“…Further data based on an elegant co-culturing system using primary liver cells pointed toward CCL5 as an important hepatic stellate cell-derived chemokine capable of mediating steatosis and pro-inflammatory responses in initially healthy hepatocytes (Kim et al 2018). Moreover, in vivo induction of CCL5 in response to high-fat diet was also shown to serve as an important regulator of vascular remodeling, revealing a role for CCL5 and its receptor in atherogenesis (Lin et al 2018). Therefore, multiple reports indicate that lipids enable fibrotic responses by influencing hepatic stellate cells.…”

Pyrogallol-Phloroglucinol-6,6-Bieckolon Attenuates Vascular Smooth Muscle Cell Proliferation and Phenotype Switching in Hyperlipidemia through Modulation of Chemokine Receptor 5

“…The expression of CCL5 and CCR5 in VSMCs treated palmitic acid (PA) was increased, and increased expression level of CCL5 or CCR5 induced VSMC proliferation and synthetic phenotype changes [ 17 ]. Expression levels of CCL5 and CCR5 in the aorta were increased in mice fed a high-fat diet (HFD) as compared to those fed a regular fat diet (NFD) [ 17 ].…”