Identification of Enzymes Responsible for the Metabolism of Heme in Human Platelets

Abstract

The major enzymes involved in the degradation of heme were identified in human platelets. It was determined that heme oxygenase activity levels in umbilical cord blood platelets were higher, whereas biliverdin reductase activity levels were comparable with that found in platelets from adults. In membranes prepared from adenosine diphosphate-activated platelets, UDP-glucuronic acid-dependent bilirubin conjugation was detected, whereas activity was negligible in unactivated platelets and undetected in serum and heat-inactivated platelets, and in platelets prepared from umbilical cord blood. Platelet fractions were analyzed by Western blot and shown to express heme oxygenase, biliverdin reductase, and UDP-glucuronosyltransferases, and there was concordance with known developmental profiles found in other tissues. Heme oxygenase expression was higher, whereas UGT expression was lower, in neonatal compared with adult platelets. These data suggest that platelets are involved in multiple steps of heme and bilirubin metabolism and that developmental regulation of these enzymes may be similar to that in other human tissues.

Carbon Monoxide and Nitric Oxide Mediate Cytoskeletal Reorganization in Microvascular Cells via Vasodilator-Stimulated Phosphoprotein Phosphorylation

“…Endothelial cells derived from either the micro-or macrovasculature (36) responded equally to CO and NO, reflecting the key roles of both HO-1 and endothelial NO synthase throughout in the entire vasculature. In contrast, platelets do not respond to CO, perhaps reflective of the low levels of heme oxygenase in adult platelets (37). By altering HO-1 and NOS gene expression, hypoxia potentially modulates the availability of these gaseous second messengers.…”

Sevoflurane attenuates pulmonary inflammation and ventilator-induced lung injury by upregulation of HO-1 mRNA expression in mice

“…During those downstream products of HO-1, CO has been demonstrated to modulate the inflammatory pathway in a variety of experimental models, reducing the production of inflammatory cytokines, while increasing the production of antiinflammatory cytokines through interaction with the MAPK pathways. 31 CO might be able to depress leukocyte adhesion through the modulation of platelet dynamics, 32 but the studies of Maulik et al 33 indicate that the antiinflammatory function of CO contributes to the production of nitric oxide, resulting in the indirect modulation of adhesive interaction.…”

Heme Oxygenase-1 Deficiency Accelerates Formation of Arterial Thrombosis Through Oxidative Damage to the Endothelium, Which Is Rescued by Inhaled Carbon Monoxide

“…In addition to vascular ECs, platelets and other circulating blood cells possess functional HO-1, 24 and CO generated by HO-1 in cultured vascular smooth muscle cells attenuates platelet activation via elevations in platelet cGMP. 23 Although platelet counts and bleeding times were not significantly different in Hmox1 Ϫ/Ϫ and Hmox1 ϩ/ϩ mice, we hypothesized that the loss of HO-1 in platelets might also contribute to accelerated thrombosis in concert with EC damage.…”

“…22 Vascular smooth muscle cellderived CO, generated by HO-1, attenuates platelet activation in vitro by increasing platelet cGMP, 23 and platelets themselves possess functionally active HO-1. 24 Deletion of Hmox1 in humans is characterized by severe and persistent endothelial cell (EC) damage with alterations in coagulation and fibrinolysis, including elevations in circulating von Willebrand Factor (vWF). 25 Inhibition of HO-1 during pulmonary ischemia/reperfusion results in additive increases in plasminogen activator inhibitor-1 and fibrin deposition.…”