Antagonism of selectin function attenuates microvascular platelet deposition and platelet-mediated myocardial injury after transient ischemia

Barrabés, José A.; Garcı́a-Dorado, David; Mirabet, Maribel; Inserte, Javier; Agulló, Luís; Soriano, Bernat; Massaguer, Anna; Padilla, Ferran; Lidón, Rosa‐Maria; Soler‐Soler, Jordi

doi:10.1016/j.jacc.2004.09.068

Cited by 61 publications

(60 citation statements)

References 29 publications

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“…19 -21 Experimental studies have shown that ischemia-reperfusion triggers platelet aggregation within coronary vessels that can be inhibited by interventions such as deletion of P-selectin or the intracellular adhesion molecule-1gene. [22][23][24] In our study, platelet accumulation in the mouse infarcted myocardium is unique in its largely extravascular location, early presence, and close association with infiltrated inflammatory cells. How do circulating platelets enter into the interstitial space of the infarcted myocardium?…”

Section: Discussionmentioning

confidence: 95%

Novel Role of Platelets in Mediating Inflammatory Responses and Ventricular Rupture or Remodeling Following Myocardial Infarction

Liu

Gao

Lü

et al. 2011

ATVB

105

125

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Objective-The goal of this study was to investigate the role of platelets in systemic and cardiac inflammatory responses and the development of postinfarct ventricular complications, as well as the efficacy of antiplatelet interventions. Methods and Results-Using a mouse myocardial infarction (MI) model, we determined platelet accumulation and severity of inflammation within the infarcted myocardium by immunohistochemistry and biochemical assays, analyzed peripheral blood platelet-leukocyte conjugation using flow cytometry, and tested antiplatelet interventions, including thienopyridines and platelet depletion. Platelets accumulated within the infarcted region early post-MI and colocalized with inflammatory cells. MI evoked early increase in circulating platelet-leukocyte conjugation mediated by P-selectin/P-selectin glycoprotein ligand-1. Antiplatelet interventions inhibited platelet-leukocyte conjugation in peripheral blood, inflammatory infiltration, content of matrix metalloproteinases or plasminogen activation, and expression of inflammatory mediators in the infarcted myocardium (all PϽ0.05) and lowered rupture incidence (PϽ0.01). Clopidogrel therapy alleviated the extent of chronic ventricular dilatation by serial echocardiography. Key Words: ischemic heart disease Ⅲ leukocytes Ⅲ platelets Ⅲ thienopyridines Ⅲ inflammation Ⅲ myocardial infarction Ⅲ ventricular rupture T he role of platelets in atherosclerotic lesions and acute coronary syndrome has been well documented. The proinflammatory actions of platelets have received increasing attention. 1,2 Platelets contribute to inflammatory responses through release of inflammatory mediators and plateletleukocyte interactions by which platelets mediate leukocyte activation and infiltration into inflamed tissues. 1,2 There are several reports of an elevated proportion of platelet-leukocyte aggregates tested ex vivo in blood samples from patients with acute coronary syndromes. [3][4][5] The current rationale for routine use of the platelet P2Y 12 receptor inhibitors thienopyridines (clopidogrel and prasugrel) is to prevent arterial thrombosis following coronary intervention. 6 Thienopyridine treatment is known to inhibit platelet-leukocyte interactions in the peripheral blood of patients with peripheral atherosclerotic vascular disease, coronary artery disease, or renal transplantation. 5,6 Myocardial infarction (MI) evokes intense inflammatory responses both systemically and within the infarcted myocardium, with adverse consequences. 7 The potential contribution of platelets to postinfarct cardiac inflammation remains unexplored. Relevant to this is the question of whether thienopyridines exert cardiac protection through inhibition of platelet's inflammatory action in the infarcted myocardium, independent of vascular thrombosis. Conclusion-PlateletsVentricular wall rupture is a fatal complication of acute MI, with a death rate of 70% to 90%. 8,9 Recent experimental studies, including ours, have provided strong evidence that wall rupture is the consequence o...

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Section: Discussionmentioning

confidence: 95%

Novel Role of Platelets in Mediating Inflammatory Responses and Ventricular Rupture or Remodeling Following Myocardial Infarction

Liu

Gao

Lü

et al. 2011

ATVB

105

125

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“…36,37 In addition, it blocks selectin-induced leukocyte and platelet accumulation to ischemic artery and prevent further damage and thrombosis. 38,39 In isolated endothelial cells, fucoidan is found to block the formation of capillary-like structures (tubes) by the endothelial cells, 14 inhibit adhesion of sickle erythrocytes to endothelium, 40 and attenuate endothelium-mediated angiogenesis. 41 Moreover, fucoidan also modulates proliferation and migration of human endothelial cells, suggesting a potential role of fucoidan as a new therapeutic agent for vascular endothelial damage.…”

Section: Discussionmentioning

confidence: 99%

Low-molecular-weight fucoidan protects endothelial function and ameliorates basal hypertension in diabetic Goto-Kakizaki rats

Cui

Zheng

Zhang

et al. 2014

Laboratory Investigation

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Endothelial dysfunction, characterized by impairment of endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) bioavailability, has been implicated in diabetic cardiovascular pathogenesis. In this study, low-molecular-weight fucoidan (LMWF), which has multiple biological activities including anti-inflammatory and anti-oxidative properties, was investigated for its protective effect against endothelial dysfunction in Goto-Kakizaki type 2 diabetic rats. LMWF (50, 100, or 200 mg/kg/day) or probucol (100 mg/kg/day) were given to diabetic rats for 12 weeks. Basal blood pressure, acetylcholine-or flow-mediated relaxation of mesenteric and paw arteries, endothelium-dependent dilation of aorta, eNOS phosphorylation, and NO production were measured using laser Doppler flowmetry, force myograph, hematoxylin and eosin staining, western blot analysis, and an NO assay. We found that LMWF robustly ameliorated the basal hypertension and impairment of endothelium-dependent relaxation in the aorta, as well as mesenteric and paw arteries in diabetic rats. In addition, the reduction in eNOS phosphorylation at Ser1177, eNOS expression, and NO production because of diabetes were partially reversed by LMWF treatment. However, probucol, a lipid-modifying drug with antioxidant properties, displayed only mild effects. Moreover, LMWF induced, in a dose-dependent manner, endotheliumdependent vasodilation and eNOS phosphorylation at Ser1177 in normal aorta, and also promoted Ser1177 phosphorylation and NO synthesis in primary cultured vasoendothelial cells. Thus, these data demonstrate for the first time that fucoidan protects vasoendothelial function and reduces basal blood pressure in type 2 diabetes rats via, at least in part, preservation of eNOS function. Fucoidan is therefore a potential candidate drug for protection of endothelium in diabetic cardiovascular complications. KEYWORDS: diabetes; endothelium-dependent vasodilation; endothelial nitric oxide synthase; low-molecular-weight fucoidan; nitric oxide Diabetic patients are at high risk of endothelial dysfunction and vascular lesions, because of multiple harmful stimuli, such as hyperglycemia, hyperlipidemia, and oxidative stress. These patients are susceptible to atherosclerosis, hypertension, and peripheral vascular disease. 1,2 It is well established that endothelium-derived nitric oxide (NO) maintains vascular homeostasis and health through vasodilation and protection of vasculature from various damaging agents. [3][4][5] Loss of NO induces increased activity of proinflammatory transcription factors, such as nuclear factor kappa B, resulting in expression of leukocyte adhesion molecules and production of chemokines and cytokines, which further promote endothelial inflammation and atherosclerosis. 5,6 Therefore, the endothelial dysfunction caused by imbalance of NO bioavailability in early-stage diabetes has been implicated as a sign or a predictor of a future cardiovascular event. [6][7][8] Mechanistically, a disturbance in endothelial NO synthase (eNOS) activity, refe...

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“…[109][110][111][112][113][114][115] Such aggregates are either released from the epicardial atherosclerotic culprit lesion and dislodged into the microcirculation or formed in the coronary microcirculation. These cellular aggregates contribute to the impairment of microvascular perfusion.…”

Section: Stasis and Intravascular Cellular Aggregatesmentioning

confidence: 99%

The Coronary Circulation as a Target of Cardioprotection

Heusch

2016

Circulation Research

206

160

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Abstract:The atherosclerotic coronary vasculature is not only the culprit but also a victim of myocardial ischemia/ reperfusion injury. Manifestations of such injury are increased vascular permeability and edema, endothelial dysfunction and impaired vasomotion, microembolization of atherothrombotic debris, stasis with intravascular cell aggregates, and finally, in its most severe form, capillary destruction with hemorrhage. In animal experiments, local and remote ischemic pre-and postconditioning not only reduce infarct size but also these manifestations of coronary vascular injury, as do drugs which recruit signal transduction steps of conditioning. Clinically, no-reflow is frequently seen after interventional reperfusion, and it carries an adverse prognosis. The translation of cardioprotective interventions to clinical practice has been difficult to date. Only 4 drugs (brain natriuretic peptide, exenatide, metoprolol, and esmolol) stand unchallenged to date in reducing infarct size in patients with reperfused acute myocardial infarction; unfortunately, for these drugs, no information on their impact on the ischemic/reperfused coronary circulation is available. (Circ Res.

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Antagonism of selectin function attenuates microvascular platelet deposition and platelet-mediated myocardial injury after transient ischemia

Abstract: The results suggest that selectin-dependent adhesion is a prominent mechanism of platelet deposition in reperfused cardiac microvessels and highlight its potential as a therapeutic target in patients with acute myocardial infarction.

Cited by 61 publications

References 29 publications

Novel Role of Platelets in Mediating Inflammatory Responses and Ventricular Rupture or Remodeling Following Myocardial Infarction

Novel Role of Platelets in Mediating Inflammatory Responses and Ventricular Rupture or Remodeling Following Myocardial Infarction

Low-molecular-weight fucoidan protects endothelial function and ameliorates basal hypertension in diabetic Goto-Kakizaki rats

The Coronary Circulation as a Target of Cardioprotection

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