Endogenous SOD2 (Superoxide Dismutase) Regulates Platelet-Dependent Thrombin Generation and Thrombosis During Aging

被引:18
|
作者
Sonkar, Vijay K. [1 ]
Eustes, Alicia S. [1 ]
Ahmed, Azaj [1 ]
Jensen, Melissa [1 ]
Solanki, Mitali V. [1 ]
Swamy, Jagadish [1 ]
Kumar, Rahul [1 ]
Fidler, Trevor P. [1 ]
Houtman, Jon C. D. [2 ]
Allen, Bryan G. [3 ]
Spitz, Douglas R. [5 ]
Abel, E. Dale [1 ,4 ]
Dayal, Sanjana [1 ,6 ]
机构
[1] Univ Iowa, Carver Coll Med, Dept Internal Med, Iowa City, IA USA
[2] Univ Iowa, Carver Coll Med, Microbiol & Immunol JCDH, Iowa City, IA USA
[3] Univ Iowa Carver Coll Med, Holden Comprehens Canc Ctr, Free Rad & Radiat Biol Program, Radiat Oncol, Iowa City, IA USA
[4] UCLA, David Geffen Sch Med, Los Angeles, CA USA
[5] Iowa City VA Healthcare Syst, Iowa City, IA USA
[6] Univ Iowa, Carver Coll Med, Dept Internal Med, 100 EMRB 200 Hawkins Dr, Iowa City, IA 52242 USA
基金
美国国家卫生研究院;
关键词
aging; genotype; mice; mitochondria; thrombin; SICKLE-CELL PATIENTS; NADPH-OXIDASE; MITOCHONDRIAL DYSFUNCTION; HYDROGEN-PEROXIDE; ACTIVATION; CALCIUM; MICE; INHIBITION; CATALASE; NOX2;
D O I
10.1161/ATVBAHA.121.317735
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background:Reactive oxygen species (ROS) contribute to platelet hyperactivation during aging. Several oxidative pathways and antioxidant enzymes have been implicated; however, their mechanistic contributions during aging remain elusive. We hypothesized that mitochondria are an important source of platelet ROS and that mitochondrial SOD2 (superoxide dismutase) protects against mitochondrial ROS-driven platelet activation and thrombosis during aging. Methods:We studied littermates of platelet-specific SOD2-knockout (SOD2(fl/fl)Pf4Cre, pSOD2-KO) and control (SOD2(fl/fl)) mice at young (4-5 months) or old (18-20 months) ages. We examined agonist-induced platelet activation, platelet-dependent thrombin generation potential, and susceptibility to in vivo thrombosis. Results:Platelet alpha(II)(b)beta 3 activation, aggregation, and adhesion were increased to similar extents in aged mice of both genotypes compared with young mice. In contrast, the age-dependent increases in mitochondrial and total cellular ROS, calcium elevation, and phosphatidylserine exposure were augmented in platelets from pSOD2-KO mice compared with control mice. Aged pSOD2-KO mice showed increased platelet-dependent thrombin generation compared with aged control mice. In vivo, aged pSOD2-KO mice exhibited enhanced susceptibility to carotid artery and pulmonary thrombosis compared to aged control mice. Adoptive transfer of platelets from aged pSOD2-KO but not aged control mice increased thrombotic susceptibility in aged host mice, suggesting a prothrombotic effect of platelet pSOD2 deficiency. Treatment with avasopasem manganese (GC4419), a SOD mimetic, decreased platelet mitochondrial pro-oxidants, cellular ROS levels, and inhibited procoagulant platelet formation and arterial thrombosis in aged mice. Conclusions:Platelet mitochondrial ROS contributes to age-related thrombosis and endogenous SOD2 protects from platelet-dependent thrombin generation and thrombosis during aging.
引用
收藏
页码:79 / 91
页数:13
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