Roles of transglutaminases in cardiac and vascular diseases.

All transglutaminases share the common enzymatic activity of transamidation, or the cross-linking of glutamine and lysine residues to form N epsilon (gamma-glutamyl) lysyl isopeptide bonds. The plasma proenzyme factor XIII is responsible for stabilizing the fibrin clot against physical and fibrinolytic disruption. Another member of the transglutaminase family, tissue transglutaminase or TG2 is abundantly expressed in cardiomyocytes, vascular cells and macrophages. The transglutaminases have a variety of functions independent of their transamidating activity. For example, TG2 binds and hydrolyzes GTP, thereby fostering signal transduction by several G protein coupled receptors. Accumulating evidence points to novel roles for factor XIII and TG2 in cardiovascular biology including: (a) modulating platelet activity, (b) regulating glucose control, (c) contributing to the development of hypertension, (d) influencing the progression of atherosclerosis, (e) regulating vascular permeability and angiogenesis (f) and contributing to myocardial signaling, contractile activity and ischemia/reperfusion injury. In this review, we summarize the cardiovascular biology of two members of the family of transglutaminases, Factor XIII and TG2.

Nicotine upregulates the expression of P2Y12 on vascular cells and megakaryoblasts.

BACKGROUND: P2Y12 is the major platelet receptor that mediates ADP-induced aggregation. P2Y12 is also expressed by vascular cells. The factors that regulate P2Y12 expression have not been determined. Since nicotine (NIC) has effects on platelet activation and vascular function, and because nicotinic and purinerigic receptors may interact, we determined whether nicotine altered P2Y12 expression. METHODS: Four cell lines (human coronary artery endothelial cells, HCAEC; human umbilical vein endothelial cells, HUVEC; human aortic smooth muscle cells, HASMC; and human megakaryoblastic cells, MEG-01) were cultured in the absence or presence of nicotine. Immunoblotting for P2Y12, P2Y2, and actin was performed. RESULTS: Nicotine, at concentrations of 0.1-1.0 microM, induced P2Y12 (but not P2Y2) expression in all the four cell lines. HASMC exhibited the greatest induction with a sixfold mean increase in P2Y12 expression in response to 0.25 microM nicotine. The induction was inhibited by nicotinic acetylcholine receptor antagonists. Healthy smokers were observed to have higher P2Y12 expression in platelet lysates compared to non-smokers. CONCLUSION: Nicotine induces the expression of P2Y12 in vascular cells and megakaryoblasts, and is mediated by nicotinic acetylcholine receptors. Smokers exhibit higher platelet P2Y12, possibly mediated via nicotine. These results may contribute to a better understanding of the effects of cigarette smoking on platelet activation and the vessel wall. CONDENSED ABSTRACT: The factors that regulate the expression of P2Y12, the platelet ADP receptor, have not been determined. Four cell lines (human coronary artery endothelial cells, HCAEC; human umbilical vein endothelial cells, HUVEC; human aortic smooth muscle cells, HASMC; and human megakaryoblastic cells, MEG-01) were cultured in the absence or presence of nicotine. Nicotine, at concentrations of 0.1-1.0 microM, induced P2Y12 expression in all the four cell lines. HASMC exhibited the greatest induction with a sixfold mean increase in P2Y12 expression in response to 0.25 microM nicotine. The induction was inhibited by nicotinic acetylcholine receptor antagonists. Healthy smokers were observed to have higher P2Y12 expression in platelet lysates compared to non-smokers. These results may contribute to a better understanding of the effects of cigarette smoking on platelet activation and the vessel wall.

Safety of abciximab administration during PCI of patients with previous stroke.

OBJECTIVES: To examine the frequency of cerebrovascular complications among patients receiving abciximab (AB) undergoing PCI with prior intracranial hemorrhage (ICH) or recent (< 2 years) ischemic strokes. BACKGROUND: AB improves clinical outcomes in high-risk patients undergoing percutaneous coronary intervention (PCI); however, the safety of AB in patients with prior stroke has not been adequately studied. METHODS: A database review of 7,244 consecutive PCIs, from 7/97 to 10/01, identified 6,190 PCIs performed with AB among which 515 interventions were performed in patients with prior stroke history [ICH or recent ischemic stroke, (n = 101) and remote (> 2 years) ischemic stroke, (n = 414)]. RESULTS: The post-PCI stroke rate was significantly higher in patients with prior stroke (2.06% vs. 0.35%, p < 0.001 for all stroke; 0.38% vs. 0.03%, p = 0.023 for ICH). The incidence of ICH among the AB-treated group was 0.065%; a history of prior stroke did not increase the incidence of ICH in the AB-treated group (0.39% vs. 0.0%, p = ns). Moreover, the post-PCI stroke rate was similar between the prior ICH or recent ischemic stroke-group and remote ischemic stroke-group (2 vs. 1.9%; OR: 1.03; 95% CI: 0.21-4.90; p = ns for all strokes; 2% vs. 1.5%; OR: 1.4; 95% CI: 0.27-6.91; p = ns for ischemic stroke). Importantly, no ICH occurred in patients with recent ischemic or any prior ICH stroke. CONCLUSIONS: Abciximab, in addition to aspirin, heparin and ADP-inhibitors does not increase the risk of stroke in patients with prior stroke undergoing PCI.

Relation of serum levels of mast cell tryptase of left ventricular systolic function, left ventricular volume or congestive heart failure.

BACKGROUND: Activated mast cells (MC) present in the myocardium of patients with cardiomyopathy may contribute to left ventricular dilatation and systolic dysfunction. We sought to determine whether peripheral levels of tryptase, an MC-specific protease, are related to indices of left ventricular size and function, as well as congestive heart failure (CHF) or coronary artery disease (CAD). METHODS AND RESULTS: Serum tryptase was measured in 85 patients undergoing cardiac catheterization with left ventriculography and coronary angiography and examined in relation to left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume (LVEDV), congestive heart failure (CHF), and angiographically evident CAD. Systemic tryptase levels were lower in patients with increased (>90 mL) LVEDV (6.2 [5.3-8.0] mcg/L versus 8.3 [6.6-10.3] mcg/L, P=.01) and in patients with CHF (6.2 [3.6-7.3] mcg/L versus 8 [6.2-10] mcg/L, P=.02) and tended to be lower in patients with depressed (<55%) LVEF (6.8 [5.2-9] mcg/L versus 8 [6.3-9.9] mcg/L, P=NS). Linear regression did not show a significant relationship between tryptase levels with either LVEF or LVEDV. Finally, tryptase levels were consistently elevated in relation to the presence of CAD. CONCLUSION: Despite increased numbers of MC in the myocardium of patients with cardiomyopathy, systemic levels of MC tryptase appear to be lower in relation to LV systolic dysfunction, LV dilatation, or clinical CHF. In contrast, the presence of angiographically significant CAD is associated with elevated systemic tryptase levels.