An octimibate derivative, Oxa17, enhances cholesterol efflux and exerts anti-inflammatory and atheroprotective effects in experimental atherosclerosis

Q2 · MEDICINE

Article

Author: Tsui, Pi-Fen ; Tsai, Min-Chien ; Lin, Feng-Yen ; Lin, Chin-Sheng ; Chern, Ching-Yuh ; Lien, Chih-Feng ; Tsai, Chien-Sung

Atherosclerotic cardiovascular diseases (ASCVDs), associated with vascular inflammation and lipid dysregulation, are responsible for high morbidity and mortality rates globally. For ASCVD treatment, cholesterol efflux plays an atheroprotective role in ameliorating inflammation and lipid dysregulation. To develop a multidisciplinary agent for promoting cholesterol efflux, octimibate derivatives were screened and investigated for the expression of ATP-binding cassette transporter A1 (ABCA1). Western blotting and qPCR analysis were conducted to determine the molecular mechanism associated with ABCA1 expression in THP-1 macrophages; results revealed that Oxa17, an octimibate derivative, enhanced ABCA1 expression through liver X receptors alpha (LXRα) activation but not through the microRNA pathway. We also investigated the role of Oxa17 in high-fat diet (HFD)-fed mice used as an in vivo atherosclerosis-prone model. In ldlr^-/- mice, Oxa17 increased plasma high-density lipoprotein (HDL) and reduced plaque formation in the aorta. Plaque stability improved via reduction of macrophage accumulation and via narrowing of the necrotic core size under Oxa17 treatment. Our study demonstrates that Oxa17 is a novel and potential agent for ASCVD treatment with atheroprotective and anti-inflammatory properties.

01 Dec 2001·British Journal of PharmacologyQ2 · MEDICINE

Prostacyclin receptor‐independent inhibition of phospholipase C activity by non‐prostanoid prostacyclin mimetics

Q2 · MEDICINE

Article

Author: Helen Wise ; Kevin B.S. Chow ; Yung Hou Wong

Chinese hamster ovary (CHO) cells were transiently transfected with the mouse prostacyclin (mIP) receptor to examine IP agonist‐mediated stimulation of [3H]‐cyclic AMP and [3H]‐inositol phosphate production.

The prostacyclin analogues, cicaprost, iloprost, carbacyclin and prostaglandin E1, stimulated adenylyl cyclase activity with EC50 values of 5, 6, 25 and 95 nM, respectively. These IP agonists also stimulated the phospholipase C pathway with 10 – 40 fold lower potency than stimulation of adenylyl cyclase.

The non‐prostanoid prostacyclin mimetics, octimibate, BMY 42393 and BMY 45778, also stimulated adenylyl cyclase activity, with EC50 values of 219, 166 and 398 nM, respectively, but failed to stimulate [3H]‐inositol phosphate production.

Octimibate, BMY 42393 and BMY 45778 inhibited iloprost‐stimulated [3H]‐inositol phosphate production in a non‐competitive manner.

Activation of the endogenously‐expressed P2 purinergic receptor by ATP led to an increase in [3H]‐inositol phosphate production which was inhibited by the non‐prostanoid prostacyclin mimetics in non‐transfected CHO cells. Prostacyclin analogues and other prostanoid receptor ligands failed to inhibit ATP‐stimulated [3H]‐inositol phosphate production.

A comparison between the IP receptor‐specific non‐prostanoid ONO‐1310 and the structurally‐related EP3 receptor‐specific agonist ONO‐AP‐324, indicated that the inhibitory effect of non‐prostanoids was specific for those compounds known to activate IP receptors.

The non‐prostanoid prostacyclin mimetics also inhibited phospholipase C activity when stimulated by constitutively‐active mutant GαqRC, Gα14RC and Gα16QL transiently expressed in CHO cells. These drugs did not inhibit adenylyl cyclase activity when stimulated by the constitutively‐active mutant GαsQL.

These results suggest that non‐prostanoid prostacyclin mimetics can specifically inhibit [3H]‐inositol phosphate production by targeting Gq/11 and/or phospholipase C in CHO cells, and that this effect is independent of IP receptors.

British Journal of Pharmacology (2001) 134, 1375–1384; doi:10.1038/sj.bjp.0704388

01 Nov 2001·Cellular SignallingQ3 · BIOLOGY

Factors affecting prostacyclin receptor agonist efficacy in different cell types

Q3 · BIOLOGY

Article

Author: Helen Wise ; Kevin B.S. Chow ; Yiu-Wing Kam

Octimibate and related nonprostanoid prostacyclin mimetics are partial agonists displaying highly tissue-specific responses. Octimibate demonstrated considerably greater efficacy for stimulation of adenylyl cyclase activity in Chinese hamster ovary cells transiently expressing mouse prostacyclin receptors (mIP-CHO cells) when compared to human SK-N-SH neuroblastoma cells, which endogenously express prostacyclin (IP) receptors. Pretreatment of both cell types with pertussis toxin (PTx) failed to influence IP agonist efficacy or potency, indicating a lack of involvement of an agonist-stimulated inhibitory G(i)-coupled pathway. Although stimulation of mIP-CHO cells with the full agonist cicaprost increased both [3H]cyclic AMP and [3H]inositol phosphate ([3H]IP) accumulation (pEC(50) values of 8.35 and 6.82, respectively), IP receptor signalling through G(q) in SK-N-SH cells was absent. Inhibition of protein kinase C (PKC) in mIP-CHO cells increased [3H]IP accumulation but had no effect on [3H]cyclic AMP accumulation. Therefore, the poor coupling of the IP receptor in SK-N-SH cells to G(q) is unlikely to explain the relatively low efficacy of octimibate for stimulating adenylyl cyclase in these cells. Furthermore, protein kinase A (PKA) inhibition appears to enhance IP receptor signalling through both G(s) and G(q) in mIP-CHO cells.

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Indication	Highest Phase	Country/Location	Organization	Date
Atherosclerosis	Phase 1	-	Sanofi	-
Thrombosis	Phase 1	-	Sanofi	-

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