Studies on effects of antioxidants on arterial thrombosis and endothelial cell injury: With special reference to Tocopherols and ApoA1 Milano
2000 (English)Doctoral thesis, comprehensive summary (Other academic)
Coronary arterial endothelial injury and thrombosis are believed to be critical factors in the pathogenesis of coronary artery disease (CAD). Experimental studies have provided evidence for au inverse relation between acute coronary events and antioxidant intake.
To study the effects and mechanisms of antioxidants (tocopherols and apoA1 Milano) on platelet aggregation and arterial thrombus formation FeCl3-induced thrombosis was induced in rats. Dietary supplementation with α-tocopherol or with γ-tocopherol-rich preparation inhibitedplatelet aggregation and delayed the time to arterial thrombosis in rats in vivo. Both α-tocopherol and γ-tocopherol-rich preparation decreased O2- generation, lipid peroxidation and LDLoxidation, and increased endogenous superoxide dismutase (SOD) and constitutive nitric oxidesynthase (cNOS) protein expression and activity. Importantly, we found that the effects of γ-tocopherol-rich preparation were more potent than those of α-tocopherol. Further, weexamined the effects of different isoforms (α-, γ- and δ-) of tocopherols and their combination onhuman platelet aggregation. α-, γ- and δ-tocopherol exerted similar inhibitory effects on human platelet aggregation by increasing cNOS activity and decreasing lipid peroxidation. The combination was more potent than α-, γ- and δ- tocopherol alone. In addition, we demonstratedthat apoA1 Milano also decreased platelet aggregation and delayed the time to thrombosis in rats.
To determine effects and mechanisms of antioxidants (tocopherols) on endothelial cell injury, cultured human coronary artery endothelial cells (HCAECs) were pretreated with α- or γ-tocopherol, and then exposed to oxidized LDL (ox-LDL, a crucial factor for CAD). Ox-LDL markedly induced apoptosis of HCAECs via degradation of IkBa and activation of transcription factor NF- kB (P65). α- or γ-tocopherol inhibited these effects of ox-LDL. α- and γ-tocopherol had similar effects. Ox-LDL upregulated gene expression of angiotensin II (Ang II, another critical factor for CAD) type 1 receptor (ATIR). Incubation of HCAECs with both ox-LDL and Ang II caused severe injury to HCAECs as determined by a cell viability test and LDH release.In this process, nuclear factor-κB (NF-κB) played a crucial role in the signal transductionmechanism. α-tocopherol inhibited ox-LDL-induced activation of NF-κB and cell injury.
These studies provide novel insights into the potential benefits of antioxidants in thrombogenesis and arterial endothelial dysfunction.
Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2000. , 47 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 936
Surgery, tocopherols, apoA1 Milano, platelet aggregation, thrombosis, superoxide dismutase, nitric oxide synthase, endothelial cells, oxidized LDL, transcription factor, apoptosis
Research subject Forensic Medicine
IdentifiersURN: urn:nbn:se:uu:diva-466ISBN: 91-554-4740-6OAI: oai:DiVA.org:uu-466DiVA: diva2:165408
2000-05-22, Lecture room, Dag Hammarskjölds väg 17, Uppsala, Uppsala, 09:15