Plasma L5 levels are elevated in ischemic stroke patients and enhance platelet aggregation

Shen, Ming-Yi; Chen, Fang Yu; Hsu, Jing‐Fang; Fu, Ru Huei; Chang, Chia Ming; Chang, Chiz Tzung; Liu, Chung Hsiang; Wu, Jia Rong; Lee, An‐Sheng; Chan, Hua‐Chen; Sheu, Joen Rong; Lin, Shinn Zong; Shyu, Woei Cherng; Sawamura, Tatsuya; Chang, Kuan Cheng; Hsu, Chung Y.; Chen, Chu Huang

doi:10.1182/blood-2015-05-646117

Cited by 76 publications

(78 citation statements)

References 51 publications

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“…6,8–10 In addition to disorders of plasma and vascular hemostasis, platelet activation plays a role in the ischemic stroke. 6,10,11 Platelet stimulation and aggregation is followed by release of potent triggers of the coagulation cascade and secondary platelet activation.…”

Section: Introductionmentioning

confidence: 99%

Contraction of Blood Clots Is Impaired in Acute Ischemic Stroke

Tutwiler

Peshkova

Andrianova

et al. 2017

ATVB

115

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Objective Obstructive thrombi or thrombotic emboli are the pathogenic basis of ischemic stroke. In vitro blood clots and in vivo thrombi can undergo platelet-driven contraction (retraction), resulting in volume shrinkage. Clot contraction can potentially reduce vessel occlusion and improve blood flow past emboli or thrombi. The aim of this work was to examine a potential pathogenic role of clot contraction in ischemic stroke. Approach and Results We employed a novel automated method that enabled us to quantify time of initiation, extent and rate of clot contraction in vitro. The main finding is clot contraction from the blood of stroke patients was reduced compared to healthy subjects. Reduced clot contraction correlated with a lower platelet count and their dysfunction, higher levels of fibrinogen and hematocrit, leukocytosis and other changes in blood composition that may affect platelet function and properties of blood clots. Platelets from stroke patents were spontaneously activated and displayed reduced responsiveness to additional stimulation. Clinical correlations with respect to severity and stroke etiology suggest that the impaired clot contraction has the potential to be a pathogenic factor in ischemic stroke. Conclusions The changeable ability of clots and thrombi to shrink in volume may be a novel unappreciated mechanism that aggravates or alleviates the course and outcomes of ischemic stroke. The clinical importance of clot or thrombus transformations in vivo and the diagnostic and prognostic value of this blood test for clot contraction needs further exploration.

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Section: Introductionmentioning

confidence: 99%

Contraction of Blood Clots Is Impaired in Acute Ischemic Stroke

Tutwiler

Peshkova

Andrianova

et al. 2017

ATVB

115

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“…In addition, serum levels of L5 were found to be significantly increased in patients with ST‐elevation myocardial infarction or stroke (Chan et al., 2013; Chang et al., 2013; Shen et al., 2015). In this study, we have further examined the biologic effects of L5 and have explored the possible involvement of L5 in premature vascular endothelial senescence.…”

Section: Introductionmentioning

confidence: 99%

Human electronegative LDL induces mitochondrial dysfunction and premature senescence of vascular cells in vivo

et al. 2018

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SummaryDysregulation of plasma lipids is associated with age‐related cardiovascular diseases. L5, the most electronegative subfraction of chromatographically resolved low‐density lipoprotein (LDL), induces endothelial dysfunction, whereas the least electronegative subfraction, L1, does not. In this study, we examined the effects of L5 on endothelial senescence and its underlying mechanisms. C57B6/J mice were intravenously injected with L5 or L1 (2 mg kg−1 day−1) from human plasma. After 4 weeks, nuclear γH2AX deposition and senescence‐associated β‐galactosidase staining indicative of DNA damage and premature senescence, respectively, were increased in the aortic endothelium of L5‐treated but not L1‐treated mice. Similar to that, in Syrian hamsters with elevated serum L5 levels induced by a high‐fat diet, nuclear γH2AX deposition and senescence‐associated β‐galactosidase staining were increased in the aortic endothelium. This phenomenon was blocked in the presence of N‐acetyl‐cysteine (free‐radical scavenger) or caffeine (ATM blocker), as well as in lectin‐like oxidized LDL receptor‐1 (LOX‐1) knockout mice. In cultured human aortic endothelial cells, L5 augmented mitochondrial oxygen consumption and mitochondrial free‐radical production, which led to ATM activation, nuclear γH2AX deposition, Chk2 phosphorylation, and TP53 stabilization. L5 also decreased human telomerase reverse transcriptase (hTERT) protein levels and activity. Pharmacologic or genetic manipulation of the reactive oxygen species (ROS)/ATM/Chk2/TP53 pathway efficiently blocked L5‐induced endothelial senescence. In conclusion, L5 may promote mitochondrial free‐radical production and activate the DNA damage response to induce premature vascular endothelial senescence that leads to atherosclerosis. Novel therapeutic strategies that target L5‐induced endothelial senescence may be used to prevent and treat atherosclerotic vascular disease.

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“…In previous studies, we have shown that the electronegativity of LDL is increased in metabolic disorders and cardiovascular diseases, such as hypercholesterolemia, diabetes, metabolic syndrome, hypertension, myocardial infarction, and stroke38394041424344. However, in our UNx model, the rats did not show arterial hypertension, myocardial fibrosis, hyperglycemia, or gross structural heart disease15.…”

Section: Discussionmentioning

confidence: 52%

Electronegative LDL-mediated cardiac electrical remodeling in a rat model of chronic kidney disease

Lee

Chen

Chan

et al. 2017

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The mechanisms underlying chronic kidney disease (CKD)–associated higher risks for life-threatening ventricular tachyarrhythmias remain poorly understood. In rats subjected to unilateral nephrectomy (UNx), we examined cardiac electrophysiological remodeling and relevant mechanisms predisposing to ventricular arrhythmias. Adult male Sprague-Dawley rats underwent UNx (n = 6) or sham (n = 6) operations. Eight weeks later, the UNx group had higher serum blood urea nitrogen and creatinine levels and a longer electrocardiographic QTc interval than did the sham group. Patch-clamp studies revealed epicardial (EPI)-predominant prolongation of the action potential duration (APD) at 50% and 90% repolarization in UNx EPI cardiomyocytes compared to sham EPI cardiomyocytes. A significant reduction of the transient outward potassium current (Ito) in EPI but not in endocardial (ENDO) cardiomyocytes of UNx rats led to a decreased transmural gradient of Ito. The reduction of Ito currents in UNx EPI cardiomyocytes was secondary to downregulation of KChIP2 but not Kv4.2, Kv4.3, and Kv1.4 protein expression. Incubation of plasma electronegative low-density lipoprotein (LDL) from UNx rats with normal EPI and ENDO cardiomyocytes recapitulated the electrophysiological phenotype of UNx rats. In conclusion, CKD disrupts the physiological transmural gradient of Ito via downregulation of KChIP2 proteins in the EPI region, which may promote susceptibility to ventricular tachyarrhythmias. Electronegative LDL may underlie downregulation of KChIP2 in CKD.

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Plasma L5 levels are elevated in ischemic stroke patients and enhance platelet aggregation

Cited by 76 publications

References 51 publications

Contraction of Blood Clots Is Impaired in Acute Ischemic Stroke

Contraction of Blood Clots Is Impaired in Acute Ischemic Stroke

Human electronegative LDL induces mitochondrial dysfunction and premature senescence of vascular cells in vivo

Electronegative LDL-mediated cardiac electrical remodeling in a rat model of chronic kidney disease

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