The cellular and molecular processes that control vascular injury responses following PCI involve a complex interplay among vascular cells and progenitor cells that control arterial remodeling, neoinitimal proliferation and reendothelialization. Drug eluting stents (DES) improve the efficacy of peructaneous coronary intervention (PCI) by modulating vascular inflammation and preventing neointimal proliferation and restenosis. Although positive effects of DES reduce inflammation and restenosis, negative effects delay reendothelialization and impair endothelial function. Delayed reendothelialization and impaired endothelial function may be linked to stent thrombosis and adverse clinical outcomes following DES use. Compared with BMS, DES may also differentially modulate mobilization, homing and differentiation of vascular progenitor cells involved reendothelialization and neointimal proliferation. The effects of DES on vascular inflammation and repair directly impact clinical outcomes with these devices and dictate requirements for extended duration dual antiplatelet therapy.

Expression of the gene encoding the S100 calcium-modulated protein family member MRP-14 (also known as S100A9) is elevated in platelets from patients presenting with acute myocardial infarction (MI) compared with those from patients with stable coronary artery disease; however, a causal role for MRP-14 in acute coronary syndromes has not been established. Here, using multiple models of vascular injury, we found that time to arterial thrombotic occlusion was markedly prolonged in Mrp14 -/-mice. We observed that MRP-14 and MRP-8/ MRP-14 heterodimers (S100A8/A9) are expressed in and secreted by platelets from WT mice and that thrombus formation was reduced in whole blood from Mrp14 -/-mice. Infusion of WT platelets, purified MRP-14, or purified MRP-8/MRP-14 heterodimers into Mrp14 -/-mice decreased the time to carotid artery occlusion after injury, indicating that platelet-derived MRP-14 directly regulates thrombosis. In contrast, infusion of purified MRP-14 into mice deficient for both MRP-14 and CD36 failed to reduce carotid occlusion times, indicating that CD36 is required for MRP-14-dependent thrombosis. Our data identify a molecular pathway of thrombosis that involves platelet MRP-14 and CD36 and suggest that targeting MRP-14 has potential for treating atherothrombotic disorders, including MI and stroke.

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Recent studies have shown that passive smoking impairs vascular endothelial function and induces oxidative stress in humans. However, in most of the previous human data regarding tobacco-induced pathophysiology, vascular endothelial dysfunction and oxidative stress have been separately assessed. This study was designed to determine the association between the acute effect of passive smoking on vascular endothelial function and in-vivo oxidative stress status. We studied 30 healthy male Japanese volunteers (32 +/- 7 years) including 15 habitual smokers and 15 nonsmokers. After baseline echocardiographic, hemodynamic recording, and blood sampling, subjects were exposed to passive smoking for 30 min. Endothelium-dependent vasodilation was measured by using % flow-mediated vasodilation (%FMD) of the brachial artery and plasma levels of 8-isoprostane was measured by enzyme immunoassay before and after the passive smoking exposure. Baseline %FMD was lower (4.3% +/- 1.2% vs. 10.9% +/- 3.1%, p < 0.001) and baseline plasma 8-isoprostane level was higher (41.5 +/- 5.8 pg/mL vs. 26.9 +/- 5.4 pg/mL, p < 0.001) in smokers than those in nonsmokers. The %FMD and 8-isoprostane level did not change after passive smoking in smokers. In nonsmokers, however, the %FMD decreased (to 5.0% +/- 1.9%, p < 0.001) and the 8-isoprostane level increased (to 37.8 +/- 9.6 pg/mL, p < 0.001) significantly after 30 min passive smoking exposure, equivalently to the levels of smokers. Sixty corrected samples before and after passive smoking exposure in all patients showed a significant negative correlation between the % FMD and the plasma 8-isoprostane levels (n = 60, r = -0.69, p < 0.001). Even 30 min of passive smoking rapidly impairs vascular endothelial function, which is associated with oxidative stress. Our data provide the pathophysiological insight for the recent epidemiological evidence about the increased risk of coronary heart disease among nonsmokers exposed to passive smoking.

Although current antiplatelet therapies provide potent antithrombotic effects, their efficacy is limited by a heightened risk of bleeding and failure to affect vascular remodeling after injury. New lines of research suggest that thrombosis and hemorrhage may be uncoupled at the interface of pathways controlling thrombosis and inflammation. Here, as one remarkable example, studies using a novel and highly selective pharmacologic inhibitor of the spleen tyrosine kinase Syk [PRT060318; 2-((1R,2S)-2-aminocyclohexylamino)-4-(m-tolylamino)pyrimidine-5-carboxamide] coupled with genetic experiments, demonstrate that Syk inhibition ameliorates both the acute and chronic responses to vascular injury without affecting hemostasis. Specifically, lack of Syk (murine radiation chimeras) attenuated shear-induced thrombus formation ex vivo, and PRT060318 strongly inhibited arterial thrombosis in vivo in multiple animal species while having minimal impact on bleeding. Furthermore, leukocyte-platelet–dependent responses to vascular injury, including inflammatory cell recruitment and neointima formation, were markedly inhibited by PRT060318. Thus, Syk controls acute and long-term responses to arterial vascular injury. The therapeutic potential of Syk may be exemplary of a new class of antiatherothrombotic agents that target the interface between thrombosis and inflammation.

Key Points PRCP influences cell growth independent of its active site. PRCP loss has reduced angiogenesis, wound healing, and ischemic/wire injury repair.

Saga Telmisartan Aggressive Research (STAR) is a single-arm, prospective multi-center trial to evaluate the effectiveness of treatment with telmisartan in patients with hypertension. A total of 197 patients with a systolic blood pressure of > or =140 or a diastolic blood pressure of > or =90 mmHg were enrolled in this study, and were prescribed 20 to 80 mg/day of telmisartan for 6 months. In all patients, both systolic and diastolic blood pressures decreased (159+/-20 to 135+/-12 mmHg, p<0.0001, 87+/-12 to 75+/-8 mmHg, p<0.0001, respectively). In addition, total cholesterol (TC) levels decreased from 200+/-40 to 188+/-33 mg/dl (p<0.05). In patients with TC > or =220 mg/dl, the change was more striking (249+/-33 to 204+/-31 mg/dl, p<0.0001). Even in patients receiving statins, TC levels still were decreased (216+/-51 to 190+/-31 mg/dl, p<0.02). In addition, TC levels were also decreased even in patients receiving telmisartan in exchange for other ARBs with TC > or =220 mg/d. Triglyceride (TG) levels were decreased (270+/-199 to 175+/-74 mg/dl, p<0.005) in patients with TG levels > or =150 mg/dl. Fasting blood glucose (FBG) was decreased (158+/-68 to 138+/-60 mg/dl, p<0.05) in patients with FBG > or =110 mg/dl. These results suggest that telmisartan may have favorable effects on lipid and glucose metabolism, in addition to lowering blood pressure. The profound effect of telmisartan to lower cholesterol suggests a potential use in hypertensive patients with dyslipidemia.