биохимия атеросклероза

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seen in IHD or diabetic patients with normal cholesterol levels [99]. Mechanism for pleiotropic effects of statins has been actively studied [100]. Growing amounts of evidence demonstrate that statins are helpful in the management of thrombotic, inflammatory, autoimmune, and neurodegenerative diseases as well as organ transplantations, in addition to atherosclerotic cardiovascular diseases. Statin treatment decreases oxLDL–LDL ratio in plasma and the thickness of carotid intima in patients with carotid artery atherosclerosis [101]. Statins reduce the levels of TF, fibrinogen, PAI-1, or platelet aggregation in patients with hypercholesterolemia or diabetes [102–105]. In a recent study conducted by our group, simvastatin reduced the levels of PAI-1 and prothrombin fragment 1 and 2 (F1+2) in plasma of type 2 diabetic patients. F1+2 is a marker of thrombin generation. Positive correlations were found between PAI-1, but not F1+2, and total or LDLcholesterol levels in diabetic patients [106]. The findings suggest that certain antithrombotic activities of statins may be secondary to cholesterol lowering, but others may be independent from cholesterol metabolism. The mechanism for statin-induced antithrombotic effects remains unclear. Results from experimental studies suggest that Ras and other prenylated G-proteins, including Rho, Rac, and Rap, are implicated in statin-mediated cellular activities [107, 108]. Statins have outstanding safety profiles. The major side effect of statins, myotoxicity, may be largely prevented by avoidance of coadministration of certain medications [109]. Statins are potential medications for preventing thrombosis in patients with hypercholesterolemia, diabetes, or increased oxidative stress.

Renin–Angiotensin Antagonists and Thrombosis

The renin–angiotensin system plays a critical role in the development of atherosclerosis, endothelial dysfunction, thrombosis, and diabetic nephropathy. Angiotensin II (AII), the major biological activator of the system, is converted from angiotensin I by angiotensin-converting enzyme (ACE). AII is a potent vasoconstrictor and a stimulator of aldosterone, an adrenal salt–water-retention hormone. AII also stimulates the proliferation of vascular cells and predisposes to vascular inflammation, thrombosis, and oxidative stress. Most biological effects of AII are mediated through AII receptor-1 (AT1) on cell surface [110]. ACE inhibitors are commonly used in the treatment of hypertension, heart failure, diabetic nephropathy, and metabolic syndrome [111]. Captopril, the first generation of ACE inhibitors, reduces platelet deposition and thrombus formation in patients with MI [112]. Ramipril reduced PAI-1 antigen and activity but did not significantly affect tPA level in MI patients in HEART study [113]. Enalapril reduced the levels of TF and MCP-1, but not TFPI, in patients with acute MI [114]. AT1 antagonists inhibit platelet aggregation and thrombus formation [115, 116]. ACE inhibitors and AT1 antagonists reduced the oxidation of LDL in humans and in several types of animal models including apolipoprotein E knockout

mice [117–122]. The inhibitory effect of AII antagonists on the oxidation of LDL may contribute, at least in part, to their antithrombotic effects.

Conclusion

Oxidative modification of LDL plays a critical role in the development of thrombosis in addition to atherosclerosis. Oxidized or minimally modified LDL cause inflammation on endothelium, which leads to a prothrombotic surface in vascular lumen. Oxidized or minimally modified LDL may activate platelet and coagulation, but reduces fibrinolytic and anticoagulation activity in vasculature (Fig. 8.3). Reduction of oxidative stress or the oxidation of LDL may be an additional therapeutic target for the prevention of thrombosis as well as atherosclerosis. The results from large trials on the effects of antioxidant vitamins for preventing cardiovascular events were not encouraging. Statins and AII antagonists may prevent thrombosis in patients with high risks through inhibiting oxidative modification of LDL.

Acknowledgments: The author thanks for the collaborations from Drs. John W. Fenton II, George King, Liam J. Murphy, Peter Cattini, and Sora Ludwig, contributions from students, postdoctoral fellows, and other staff working in his laboratories to relevant studies and grant supports from Canadian Institute of Health Research, Canadian Diabetes Association, Heart Stroke Foundation of Canada, Manitoba Medical Service Foundation, Manitoba Health Research Council, University of Manitoba, and Dr. Paul Tholackson Foundation, and research space provided by Health Sciences Centre Foundation.

Atherosclerosis

Thrombosis

FIGURE 8.3. Scheme for relationships between oxidatively modified LDL, atherosclerosis, and thrombosis.

160 Garry X. Shen

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