title: Altered expression of platelet proteins and calpain activity mediate hypoxia-induced prothrombotic phenotype.
abstract: Oxygen-compromised environments, such as high altitude, air travel, and sports, and pathological conditions, such as solid tumors, have been suggested to be prothrombotic. Despite the indispensable role of platelets in thrombus formation, the studies linking hypoxia, platelet reactivity, and thrombus formation are limited. In the present study, platelet proteome/reactivity was analyzed to elucidate the acute hypoxia-induced prothrombotic phenotype. Rats exposed to acute simulated hypoxia (282 torr/8% oxygen) demonstrated a decreased bleeding propensity and increased platelet reactivity. Proteomic analysis of hypoxic platelets revealed 27 differentially expressed proteins, including those involved in coagulation. Among these proteins, calpain small subunit 1, a 28-kDa regulatory component for calpain function, was significantly upregulated under hypoxic conditions. Moreover, intraplatelet Ca(2+) level and platelet calpain activity were also found to be in accordance with calpain small subunit 1 expression. The inhibition of calpain activity demonstrated reversal of hypoxia-induced platelet hyperreactivity. The prothrombotic role for calpain was further confirmed by an in vivo model of hypoxia-induced thrombosis. Interestingly, patients who developed thrombosis while at extreme altitude had elevated plasma calpain activities and increased soluble P-selectin level. In summary, this study suggests that augmented calpain activity is associated with increased incidence of thrombosis under hypoxic environments.
authors.affiliation: Defense Institute of Physiology & Allied Sciences, Timarpur, Delhi, India;
authors.forename: Tarun
authors.initials: T
authors.lastname: Tyagi
authors.forename: Shadab
authors.initials: S
authors.lastname: Ahmad
authors.forename: Neha
authors.initials: N
authors.lastname: Gupta
authors.forename: Anita
authors.initials: A
authors.lastname: Sahu
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Ahmad
authors.forename: Velu
authors.initials: V
authors.lastname: Nair
authors.forename: Tathagat
authors.initials: T
authors.lastname: Chatterjee
authors.forename: Nitin
authors.initials: N
authors.lastname: Bajaj
authors.forename: Shantanu
authors.initials: S
authors.lastname: Sengupta
authors.forename: Lilly
authors.initials: L
authors.lastname: Ganju
authors.forename: Shashi Bala
authors.initials: SB
authors.lastname: Singh
authors.forename: Mohammad Z
authors.initials: MZ
authors.lastname: Ashraf
mesh_terms: D000328:Adult; D000532:Altitude Sickness / Q000378:metabolism; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D002154:Calpain / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D008297:Male; D015539:Platelet Activation / Q000502:physiology; D020543:Proteome / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019851:Thrombophilia / Q000378:metabolism; D013927:Thrombosis / Q000378:metabolism*
chemical_list: D020543:Proteome; D002154:Calpain; C587939:Capns1 protein, rat; C527669:CAPNS1 protein, human