Objective-Restenosis after angioplasty remains a major clinical problem. Prostaglandin E 2 (PGE 2 ) plays an important role in vascular homeostasis. The PGE 2 receptor E-prostanoid 2 (EP2) is involved in the proliferation and migration of various cell types. We aimed to determine the role of EP2 in the pathogenesis of neointimal formation after vascular injury. Methods and Results-Wire-mediated vascular injury was induced in the femoral arteries of male wild-type (EP2ϩ/ϩ) and EP2 gene-deficient (EP2Ϫ/Ϫ) mice. In EP2ϩ/ϩ mice, EP2 mRNA expression was increased in injured vessels for at least 4 weeks after vascular injury. Neointimal hyperplasia was markedly accelerated in EP2Ϫ/Ϫ mice, which was associated with increased proliferation and migration of vascular smooth muscle cells (VSMCs) and increased cyclin D1 expression in the neointima layer. Platelet-derived growth factor-BB (PDGF-BB) treatment resulted in more significant cell proliferation and migration in VSMCs of EP2Ϫ/Ϫ mice than in those of EP2ϩ/ϩ mice. Activation and overexpression of EP2 attenuated PDGF-BB-elicited cell proliferation and migration, induced G 1 3 S-phase arrest and reduced PDGF-BB-stimulated extracellular signal-regulated kinase phosphorylation in EP2ϩ/ϩ VSMCs. Conclusion-These findings reveal a novel role of the EP2 receptor in neointimal hyperplasia after arterial injury. The EP2 receptor may represent a potential therapeutic target for restenosis after angioplasty. (Arterioscler Thromb Vasc Biol. 2011;31:1739-1747.)Key Words: angioplasty Ⅲ eicosanoids Ⅲ prostaglandins Ⅲ receptors Ⅲ restenosis P ercutaneous transluminal coronary angioplasty (PTCA) has been widely used for treating coronary atherosclerosis. However, many patients undergoing PTCA experience postangioplasty restenosis. 1 Although new devices for dilatation of stenosed arteries have lowered the incidence of acute complications, restenosis remains a major obstacle in the long-term outcome of PTCA interventions. 2 Restenosis is defined as the healing response of the arterial wall to mechanical injury and consists of 2 main processes: neointimal hyperplasia (smooth muscle migration/proliferation and extracellular matrix deposition) and vessel remodeling. 3 Platelet-derived growth factor-BB (PDGF-BB), an important growth factor released from platelets and leukocytes, plays a critical role in intimal hyperplasia after vascular injury. 4,5 An enormous amount of research has elucidated the molecular pathways involved in neointimal formation and vascular remodeling after vascular injury and has greatly advanced our understanding of the mechanisms contributing to the pathogenesis of restenosis. 6 -8 These efforts have led to many new strategies for effective prevention and treatment options for restenosis.Prostaglandin E 2 (PGE 2 ), a major arachidonic acid metabolite, is produced in the vasculature via a mechanism dependent on cyclooxygenase (COX) and prostaglandin E synthase. PGE 2 has important roles in the regulation of blood pressure, inflammatory response, immune response, an...

Retinoic acid receptor (RAR) has been implicated in pathological stimuli-induced cardiac remodeling. To determine whether the impairment of RARα signaling directly contributes to the development of heart dysfunction and the involved mechanisms, tamoxifen-induced myocardial specific RARα deletion (RARαKO) mice were utilized. Echocardiographic and cardiac catheterization studies showed significant diastolic dysfunction after 16 wks of gene deletion. However, no significant differences were observed in left ventricular ejection fraction (LVEF), between RARαKO and wild type (WT) control mice. DHE staining showed increased intracellular reactive oxygen species (ROS) generation in the hearts of RARαKO mice. Significantly increased NOX2 (NADPH oxidase 2) and NOX4 levels and decreased SOD1 and SOD2 levels were observed in RARαKO mouse hearts, which were rescued by overexpression of RARα in cardiomyocytes. Decreased SERCA2a expression and phosphorylation of phospholamban (PLB), along with decreased phosphorylation of Akt and Ca2+/calmodulin-dependent protein kinase II δ (CaMKII δ) was observed in RARαKO mouse hearts. Ca2+ reuptake and cardiomyocyte relaxation were delayed by RARα deletion. Overexpression of RARα or inhibition of ROS generation or NOX activation prevented RARα deletion-induced decrease in SERCA2a expression/activation and delayed Ca2+ reuptake. Moreover, the gene and protein expression of RARα was significantly decreased in aged or metabolic stressed mouse hearts. RARα deletion accelerated the development of diastolic dysfunction in streptozotocin (STZ)-induced type 1 diabetic mice or in high fat diet fed mice. In conclusion, myocardial RARα deletion promoted diastolic dysfunction, with a relative preserved LVEF. Increased oxidative stress have an important role in the decreased expression/activation of SERCA2a and Ca2+ mishandling in RARαKO mice, which are major contributing factors in the development of diastolic dysfunction. These data suggest that impairment of cardiac RARα signaling may be a novel mechanism that is directly linked to pathological stimuli-induced diastolic dysfunction.

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Diabetic cardiomyopathy (DCM), a significant contributor to morbidity and mortality in diabetic patients, is characterized by ventricular dysfunction, in the absence of coronary atherosclerosis and hypertension. There is no specific therapeutic strategy to effectively treat patients with DCM, due to a lack of a mechanistic understanding of the disease process. Retinoic acid, the active metabolite of vitamin A, is involved in a wide range of biological processes, through binding and activation of nuclear receptors: retinoic acid receptors (RAR) and retinoid X receptors (RXR). RAR/RXR-mediated signaling has been implicated in the regulation of glucose and lipid metabolism. Recently, it has been reported that activation of RAR/RXR has an important role in preventing the development of diabetic cardiomyopathy, through improving cardiac insulin resistance, inhibition of intracellular oxidative stress, NF-κB-mediated inflammatory responses and the renin-angiotensin system. Moreover, downregulated RAR/RXR signaling has been demonstrated in diabetic myocardium, suggesting that impaired RAR/RXR signaling may be a trigger to accelerate diabetes-induced development of DCM. Understanding the molecular mechanisms of retinoid receptors in the regulation of cardiac metabolism and remodeling under diabetic conditions is important in providing the impetus for generating novel therapeutic approaches for the prevention and treatment of diabetes-induced cardiac complications and heart failure.