Altered Lipid Metabolism Improves Healing and Reduces Inflammation
Researchers here demonstrate that tinkering with the normal operation of lipid metabolism in mice can improve healing and reduce inflammation following a heart attack, suggesting that the approach may have broader applications in cardiovascular disease.
Two immune responses are important for recovery after a heart attack - an acute inflammatory response that attracts leukocyte immune cells to remove dead tissue, followed by a resolving response that allows healing. Failure of the resolving response can allow a persistent, low-grade nonresolving inflammation, which can lead to progressive acute or chronic heart failure. Using a mouse heart attack model, researchers have shown that knocking out one particular lipid-modifying enzyme, along with a short-term dietary excess of a certain lipid, can improve post-heart attack healing and clear inflammation.
Why are lipids and lipid-modifying enzymes important in inflammation and resolving inflammation? Three key lipid modifying enzymes in the body change the lipids into various signaling agents. Some of these signaling agents regulate the triggering of inflammation, and others promote the reparative pathway. The lipids modified by the enzymes are two types of essential fatty acids that come from food, since mammals cannot synthesize them. One is n-6 or omega-6 fatty acids, and the other type is n-3 or omega-3 fatty acids. The balance of these two types is important. The three main lipid-modifying enzymes compete with each other to modify whatever fatty acids are available from the diet. So, researchers asked, what will happen if we knock out one of the key enzymes, the 12/15 lipoxygenase? They reasoned that this would increase the metabolites produced by the other two main enzymes, cyclooxygenase and cytochrome P450 because they no longer had to compete with 12/15 lipoxygenase for lipids to modify. This might be a benefit because those signaling lipids produced through the cyclooxygenase and cytochrome P450 pathways were already known to lead to major resolution promotion factors for post-heart attack healing.
The researchers found that knocking out the 12/15 lipoxygenase and feeding the mice a short-term excess of polyunsaturated fatty acids led to increased leukocyte clearance after experimental heart attack, meaning less chronic inflammation. It also improved heart function, increased the levels of bioactive lipids during the reparative phase of healing, and led to higher levels of reparative cytokine markers. Additionally, the heart muscle showed less of the fibrosis that is a factor in heart failure. Besides congestive heart failure, persistent inflammation aggravates a vicious cycle in many cardiovascular diseases. Further mechanistic studies are warranted to develop novel targets for treatment and to find therapies that support the onset of left ventricle healing and prevent heart failure pathology.