Acyclic Retinoid Inhibits Neointima Formation Through Retinoic Acid Receptor Beta-Induced Apoptosis

Abstract

Objectives-Acyclic retinoid (ACR) is a synthetic retinoid with a high safety profile that has been pursued with high expectations for therapeutic use in prevention (recurrence) and treatment of malignancies. With the objective of addressing the therapeutic potential in the cardiovasculature, namely neointima formation, effects of ACR on neointima formation and the involved mechanisms were investigated. Methods and Results-ACR was administered to cuff-injured mice which showed inhibition of neointima formation.Investigation of involved mechanisms at the cellular and molecular levels showed that ACR induces apoptosis of neointimal cells and this to be mediated by selective induction of retinoic-acid receptor ␤ (RAR␤) which shows growth inhibitory and proapoptotic effects on smooth muscle cells. Key Words: smooth muscle cell Ⅲ cell growth Ⅲ retinoid R etinoids are natural and synthetic derivatives of vitamin A which modulate growth, apoptosis, and differentiation of cells. 1 Many retinoids have been pursued from therapeutic standpoints with the aim of chemotherapy of cancer, leukemia, and prevention of atherosclerosis. 1 The biological effects of retinoids are mainly mediated by their receptors, retinoicacid receptor (RAR) and retinoic-X receptor (RXR). 2 RAR interacts with both all-trans retinoic acid (ATRA) and 9-cis retinoic acid (9cRA), and has 3 isoforms (␣, ␤, and ␥). 2 Among the retinoid receptors, RAR␤ plays a critical role in mediating the effects of retinoid on cell growth and tumor inhibition in various cancer cells. 3,4 RAR␤ expression diminishes with development of esophageal squamous cell carcinoma. 4 Induction of RAR␤ by ATRA and overexpression of RAR␤ also play important roles in mediating the growth-inhibitory effects of ATRA in human lung squamous cell carcinoma. 3 These findings indicate that modulation of expression of RAR␤ critically regulates cell growth inhibition. The role of RAR␤ in vascular SMCs (smooth muscle cells), however, has not been previously addressed. Conclusion-WeAcyclic retinoid (ACR) is a novel synthetic RAR-selective retinoid (supplemental Table I) which has been shown to inhibit the growth of hepatoma cells in vivo and in vitro. 5 ACR has been shown to inhibit the recurrence of hepatocellular carcinoma with oral administration in clinical trials, and has a high safety profile causing less side effects than other retinoids. 6 Recently, ACR has been shown to preferentially act on and to elicit biological effects mainly through RAR␤. 7,8 At the cellular level, ACR induces apoptosis in hepatoma cells. 9,10 ACR is therefore well-defined and safe, and is thus an attractive retinoid for therapeutic use. However, its effects on vascular remodeling have not been studied.In the present study, we investigated whether ACR shows effects on neointima formation. We also addressed the mechanism of action of ACR in the vasculature, namely through effects on expression of RARs in SMCs with a focus on the biological role of RAR␤. We show that expression of RAR␤ as induced by ACR exerts i...

Acyclic retinoid inhibits angiogenesis by suppressing the MAPK pathway

“…21,22 On the other hand, accumulating evidence shows that ACR, but not atRA, has apoptosisinducing activity in HCC cells, as well as in smooth muscle cells and vascular neointima. 23,24 We found that ACR acts as either a kinase inhibitor or a phosphatase stimulator and prevents hyperphosphorylation of RXR, 9 and now VEGFR2. In this context, we speculate that ACR resembles geranylgeraniol in terms of its isoprenoid-like structure, which has been implicated in the modulation of many phosphorylation/dephosphorylation signaling.…”

Krüppel-like Factor 4 Inhibits Proliferation by Platelet-derived Growth Factor Receptor β-mediated, Not by Retinoic Acid Receptor α-mediated, Phosphatidylinositol 3-Kinase and ERK Signaling in Vascular Smooth Muscle Cells

“…Retinoids modulate cell growth, apoptosis, and differentiation (40,43). The biological effects of retinoids are mainly mediated by their receptors, i.e.…”

Acyclic retinoid inhibits functional interaction of transcription factors Krüppel‐like factor 5 and retinoic acid receptor‐alpha

“…3C). Moreover, we investigated the effects of ACR on cell apoptosis as we have recently shown that ACR induces apoptosis [5], which showed that ACR markedly induces apoptosis of 3T3‐KLF5 stable cells in a dose‐dependent manner as compared to the dose‐dependent yet very marginal increases as induced by ATRA (Fig. 3D).…”

“…Of the synthetic retinoids, acyclic retinoid (ACR) has a high safety profile and is presently being pursued for clinical use an oral anti‐cancer agent for hepatomas [3,4]. We have recently shown that ACR regulates cardiovascular remodeling [5]. Briefly, ACR attenuated neointimal formation by selectively inducing retinoic acid receptor‐beta (RARβ), which is a pro‐apoptotic factor, in vascular cells, which results in apoptosis of neointima cells and thus attenuates vascular remodeling [5].…”

“…We have recently shown that ACR regulates cardiovascular remodeling [5]. Briefly, ACR attenuated neointimal formation by selectively inducing retinoic acid receptor‐beta (RARβ), which is a pro‐apoptotic factor, in vascular cells, which results in apoptosis of neointima cells and thus attenuates vascular remodeling [5]. In the present study, we examined whether ACR may also regulate interaction of KLF5 and RARα similar to other synthetic retinoids which may be an alternative pathway whereby ACR exerts its functions on cardiovascular remodeling.…”