Salt-Inducible Kinase 3 Promotes Vascular Smooth Muscle Cell Proliferation and Arterial Restenosis by Regulating AKT and PKA-CREB Signaling

Objective: Arterial restenosis is the pathological narrowing of arteries after endovascular procedures, and it is an adverse event that causes patients to experience recurrent occlusive symptoms. Following angioplasty, vascular smooth muscle cells (SMCs) change their phenotype, migrate, and proliferate, resulting in neointima formation, a hallmark of arterial restenosis. SIKs (salt-inducible kinases) are a subfamily of the AMP-activated protein kinase family that play a critical role in metabolic diseases including hepatic lipogenesis and glucose metabolism. Their role in vascular pathological remodeling, however, has not been explored. In this study, we aimed to understand the role and regulation of SIK3 in vascular SMC migration, proliferation, and neointima formation. Approach and Results: We observed that SIK3 expression was low in contractile aortic SMCs but high in proliferating SMCs. It was also highly induced by growth medium in vitro and in neointimal lesions in vivo. Inactivation of SIKs significantly attenuated vascular SMC proliferation and up-regulated p21 CIP1 and p27 KIP1 . SIK inhibition also suppressed SMC migration and modulated actin polymerization. Importantly, we found that inhibition of SIKs reduced neointima formation and vascular inflammation in a femoral artery wire injury model. In mechanistic studies, we demonstrated that inactivation of SIKs mainly suppressed SMC proliferation by down-regulating AKT (protein kinase B) and PKA (protein kinase A)-CREB (cAMP response element-binding protein) signaling. CRTC3 signaling likely contributed to SIK inactivation-mediated antiproliferative effects. Conclusions: These findings suggest that SIK3 may play a critical role in regulating SMC proliferation, migration, and arterial restenosis. This study provides insights into SIK inhibition as a potential therapeutic strategy for treating restenosis in patients with PAD.

Photothermal Therapy Based on CuS Nanoparticles for Alleviating Arterial Restenosis Induced by Mechanical Injury of Endovascular Treatment

CuS nanoparticles (NPs) as an effective near-infrared absorption agent have been widely applied in the photothermal therapy (PTT) of cancer. However, little is known about the application of CuS NP-based PTT in alleviating arterial inflammation and restenosis, which affects the long-term prognosis of endovascular treatment. In this study, CuS NPs were synthesized and used as PTT nanoplatform for ameliorating arterial inflammation induced by mechanical injury of endovascular treatment. The macrophages possess powerful phagocytosis toward CuS NPs is evidenced by intracellular transmission electron microscopic imaging. As illustrated from Cell Counting Kit-8 assay and calcein AM/PI staining, an efficient depletion of macrophages by CuS NPs coculture combined with the irradiation with a 915-nm near-infrared laser was achieved. The endarterium injury/inflammation model was established by insertion of a 29G needle (BD Insulin Syringe Ultra-Fine®) to the left common carotid artery of an apolipoprotein E knockout mouse to mimic endarterium damage after endovascular treatment. Local injection of CuS NPs around the left common carotid artery followed by irradiation with a 915-nm INR laser significantly depleted infiltrated macrophages and alleviated arterial stenosis. This work emphasizes the role of CuS NPs as a PTT agent in post-injury remodeling of the arterial wall and provides an attractive target macrophage that can be depleted to alleviate arterial restenosis.

Microbial Colonization of Germ‐Free Mice Restores Neointimal Hyperplasia Development After Arterial Injury

Background The potential role of the gut microbiome in cardiovascular diseases is increasingly evident. Arterial restenosis attributable to neointimal hyperplasia after cardiovascular procedures such as balloon angioplasty, stenting, and bypass surgery is a common cause of treatment failure, yet whether gut microbiota participate in the development of neointimal hyperplasia remains largely unknown. Methods and Results We performed fecal microbial transplantation from conventionally raised male C57BL/6 mice to age‐, sex‐, and strain‐matched germ‐free mice. Five weeks after inoculation, all mice underwent unilateral carotid ligation. Neointimal hyperplasia development was quantified after 4 weeks. Conventionally raised and germ‐free cohorts served as comparison groups. Conclusions Germ‐free mice have significantly attenuated neointimal hyperplasia development compared with conventionally raised mice. The arterial remodeling response is restored by fecal transplantation. Our results describe a causative role of gut microbiota in contributing to the pathogenesis of neointimal hyperplasia.