Omega-3 Polyunsaturated Fatty Acids (n-3 PUFAs) in Cardiovascular Diseases (CVDs) and Depression: The Missing Link?

Abstract

Background. Based on epidemiological data, clinical trials, and meta-analytic reviews, omega-3 polyunsaturated fatty acids (n-3 PUFAs) seem to be a biological link between depression and cardiovascular diseases (CVDs). Presentation. Involvement of n-3 PUFAs in depression and CVDs may be associated with a chronic, low-grade, inflammation. We hypothesize that n-3 PUFAs link depression and CVDs via "PUFA-prostaglandin E2 (PGE2) cascade." Testing. To further support our hypothesis, case-control studies are needed to test the role of COX2 and PLA2 functions in depression and in CVDs. In addition, the effects of n-3 PUFAs on cardiovascular markers in depression and on depressive symptoms in CVDs should be investigated in clinical trials. Finally, the effects of manipulating COX2 and PLA2 functions on depression-like behaviors and cardiovascular functions could be explored in animal studies. Implications. n-3 PUFAs might be a promising treatment for both cardiovascular diseases and depression via its anti-inflammatory, cardioprotective, and neuroprotective effects.

Figure 1

Genetic and environmental factors related to n-3 fatty acids hypothesis of depression and CVD. The levels of n-3 PUFAs (n-3 EPA and n-3 DHA) are influenced by genetic (e.g., PLA2 and COX2 genes on chromosome 1) and environmental (diet, inflammation, or cytokines) factors. n-3 DHA plays a major role in neuronal membrane stability and functions of signal transduction and neurotransmission; meanwhile, n-3 PUFAs are important in balancing the immune and inflammatory functions by antagonizing membrane n-6 AA and reducing PGE2 synthesis. PLA2 and COX2 are the two key enzymes for the PUFA metabolism and PGE2 synthesis. PLA2 is a large family of enzymes, with the iPLA2 (Ca2+-independent PLA2) preferentially functioning in n-3 DHA metabolism and the cPLA2 (cytosolic PLA2) preferentially in n-6 AA and n-3 EPA metabolism. COX2 is the key enzyme that converts n-6 AA to PGE2, while 5-LO converts n-6 AA to LTB4. PGE2 and LTB4 participate in immunoregulation, which might be associated with somatic symptoms of depression and physical manifestations of CVD. Proinflammatory cytokines, such as IL-2 and IFN-γ, activate PLA2 or COX2 and in turn increase levels of n-6 AA. MDR PGP has effects in depression by reducing the access of glucocorticoids to the brain. n-3 PUFAs, on the other hand, can inhibit MDR PGP. Enhancement is shown by a solid line, attenuation by a dashed line. COX2 = cyclooxygenase 2; PLA2 = phospholipase A2; 5-LO = 5-lipoxyge; MDR PGP = multidrug resistance p-glycoprotein; CVD = cardiovascular disease.