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Can COX-2 inhibitor-induced increase in cardiovascular disease risk be modified by essential fatty acids?
1UND Life Sciences, #205, 2477 Overlook Road, Cleveland Heights, OH 44106, USA.
Abstract:
Selective COX-2 inhibitors increase the risk of myocardial infarction and stroke. This has been attributed to their ability to inhibit endothelial COX-2 derived prostacyclin (PGI2) but not platelet COX-1 derived thromboxane A2 (TXA2). On the other hand, aspirin blocks both COX-1 and COX-2 enzymes without decreasing PGI2 but blocks TXA2 synthesis that explains its beneficial action in the prevention of coronary heart disease (CHD). The inhibitory action of aspirin on COX-1 and COX-2 enzymes enhances the tissue concentrations of dihomo-gamma-linolenic acid (DGLA), arachidonic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). These fatty acids form precursors to PGE1, PGI2, PGI3, lipoxins (LXs), and resolvins that have anti-inflammatory actions. In contrast, increase in the concentrations of DGLA, AA, EPA, and DHA is much less with specific COX-2 inhibitors since they do not block the formation of eicosanoids through COX-1 pathway. COX-2 inhibitors interfere with the formation of LXs and resolvins that have neuroprotective and cardioprotective actions. EPA and PGI2 have anti-arrhythmic action. EPA, DHA, and AA augment eNO formation that prevents atherosclerosis. This suggests that COX-2 inhibitors increase cardiovascular and stroke risk by interfering with the formation of eNO, PGI2, LXs, and resolvins and implies that combining EFAs with COX-2 inhibitors could prevent these complications.
Insights
Selective COX-2 inhibitors raise heart attack and stroke risks by blocking beneficial compounds. Combining them with essential fatty acids (EFAs) may prevent these cardiovascular complications.
Area of Science:
- Cardiovascular Pharmacology
- Inflammation and Resolution Biology
Background:
- Selective COX-2 inhibitors are linked to increased myocardial infarction and stroke risk.
- This risk is associated with inhibiting endothelial prostacyclin (PGI2) while sparing platelet thromboxane A2 (TXA2).
- Aspirin, by inhibiting both COX-1 and COX-2, offers cardioprotection by blocking TXA2 and enhancing anti-inflammatory mediators.
Purpose of the Study:
- To investigate the mechanisms behind COX-2 inhibitor-induced cardiovascular risks.
- To explore the role of essential fatty acids (EFAs) and their metabolites in cardiovascular health.
- To evaluate the potential of combining EFAs with COX-2 inhibitors to mitigate cardiovascular risks.
Main Methods:
- Comparative analysis of COX-1 and COX-2 inhibition effects on eicosanoid synthesis.
- Assessment of tissue concentrations of dihomo-gamma-linolenic acid (DGLA), arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA).
- Evaluation of the impact on the formation of prostaglandins, lipoxins (LXs), resolvins, and nitric oxide (NO).
Main Results:
- Aspirin increases DGLA, AA, EPA, and DHA, leading to anti-inflammatory PGI2, PGI3, and LXs.
- Selective COX-2 inhibitors show a lesser increase in these fatty acids and interfere with LXs and resolvins.
- COX-2 inhibitors impair the formation of cardioprotective and neuroprotective mediators, including PGI2, LXs, resolvins, and nitric oxide (NO).
Conclusions:
- Selective COX-2 inhibitors increase cardiovascular and stroke risk by disrupting the formation of NO, PGI2, LXs, and resolvins.
- The beneficial actions of aspirin are partly due to enhanced formation of anti-inflammatory and protective lipid mediators.
- Combining essential fatty acids (EFAs) with COX-2 inhibitors may offer a strategy to prevent associated cardiovascular complications.
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