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Bioactive Lipids and Receptors


Introduction of bioactive lipids and receptors

Bioactive lipids in the human body mainly refer to eicosanoids. It is a large class of biologically active unsaturated fatty acids produced by the oxidation of twenty carbon polyunsaturated fatty acids. It is an important inflammatory factor widely present in body fluids and tissues, regulating many physiological and pathological processes in the body. They are a large class of hormone analogue produced by many mammalian tissues, and they only work in the organs that are produced, so they are called autocrine regulatory molecules. Eicosanoids have multiple subfamilies, including most prominently the prostaglandins, thromboxanes, and leukotrienes.

Bioactive Lipids and Receptors

The function of bioactive Lipids and receptors

Eicosanoids represent a diverse family of lipid mediators with fundamental roles in physiology and disease. Within the eicosanoid superfamily, prostanoids are specifically derived from arachidonic acid by the enzyme cyclooxygenase (COX). COX has two isoforms; COX-1 and COX-2. COX-2 is the therapeutic target for the nonsteroidal anti-inflammatory drug (NSAID) class of pain medications. Prostanoids were first discovered by Sir John Vane in 1976, and it is one of the fundamental protective cardiovascular pathways. Since this time, researchers learnt much about how eicosanoids, COX enzymes and prostacyclin function in the cardiovascular system, for example, to harness the power of prostacyclin as therapy to treat pulmonary arterial hypertension and peripheral vascular disease. Thromboxane (Thromboxane is named for its role in clot formation) is a member of the family of eicosanoids. They have two major categories are thromboxane A2 and thromboxane B2. They are produced by platelets and play a role in clot formation. In platelets, thromboxane-A synthase will convert the arachidonic acid derivative prostaglandin H2 to thromboxane. Thromboxane acts by binding to any of thromboxane receptors and G-protein-coupled receptors coupled to the G protein Gq. After the interaction between thromboxane and its receptors, it will promote vasoconstriction and platelet aggregation. It is in homeostatic balance in the circulatory system with prostacyclin, a related compound. The mechanism of secretion of thromboxanes from platelets remains unclear. They operate in the formation of blood clots and reduce blood flow to the site of a clot. If the cap of a vulnerable plaque erodes or ruptures, as in myocardial infarction, platelets stick to the damaged lining of the vessel and to each other within seconds and form a plug. These "Sticky platelets" secrete several chemicals, including thromboxane A2 that stimulate vasoconstriction, reducing blood flow at the site. Leukotrienes are a member of eicosanoid family, and it produces in leukocytes by the oxidation of arachidonic acid (AA) and the essential fatty acid eicosapentaenoic acid (EPA) by the enzyme arachidonate 5-lipoxygenase. In leukocytes, they are inflammatory mediators. Leukotrienes use lipid signaling to convey information to either the cell producing them (autocrine signaling) or neighboring cells (paracrine signaling) in order to govern immune responses. Production of leukotrienes is usually accompanied by the production of histamine and prostaglandins, which also act as inflammatory mediators. Leukotrienes act principally on a subfamily of G protein-coupled receptors. They may also operate on peroxisome proliferator-activated receptors. Leukotrienes are associated with asthmatic and allergic reactions and act to sustain inflammatory reactions. Recent research points that 5-lipoxygenase plays a role in cardiovascular and neuropsychiatric illnesses.

In addition, there are a distinct class bioactive lipids includes lysophosphatidic acid, sphingosine-1-phosphate and endocannabinoid. lysophosphatidic acid acts as a potent mitogen due to its activation of three high-affinity G-protein-coupled receptors; sphingosine-1-phosphate play role in the mediation of blood borne lipid; endocannabinoid is involved in regulating a variety of physiological and cognitive processes, such as, fertility, pregnancy, appetite, pain-sensation, mood, memory and so on.

Clinical significance

Prostaglandin has currently ten known receptors on various cell types. Prostaglandin receptors are a sub-family of cell surface seven-transmembrane receptors and G-protein-coupled receptors. These receptors are termed DP1-2, EP1-4, FP, IP1-2, and TP, corresponding to the corresponding prostaglandin. According to previous studies, prostaglandin can cause constriction or dilation in vascular smooth muscle cells and aggregation or disaggregation of platelets. So synthetic prostaglandins are used to prevent closure of patent ductus arteriosus in newborns with particular cyanotic heart defects and act as a vasodilator in severe Raynaud's phenomenon or ischemia of a limb in clinical. In addition, it plays an important part in pulmonary hypertension. These mean that prostaglandins are closely related to cardiovascular.

The results indicated that the vasoconstriction caused by thromboxanes ( TxA) plays a role in Prinzmetal's angina. Omega-3 fatty acids(polyunsaturated fatty acids) are metabolized to produce higher levels of Thromboxane A3, which is relatively less potent than thromboxane A2( Thromboxane A2, produced by activated platelets, has prothrombotic properties, stimulating activation of new platelets as well as increasing platelet aggregation) and PGI3; therefore, there is a balance shift toward inhibition of vasoconstriction and platelet aggregation. It believes that this shift in balance lowers the incidence of myocardial infarction (heart attack) and stroke. Vasoconstriction is a phenomenon by various proinflammatory effects exerted by TxA on tissue microvasculature. These are the probable reason why the TxA is pathogenic in various diseases, such as ischemia-reperfusion injury, hepatic inflammatory processes, acute hepatotoxicity etc. TxB2, a stable degradation product of TxA2, plays a role in acute hepatoxicity induced by acetaminophen.

Additionally, leukotrienes contribute to the pathophysiology of asthma, especially in patients with aspirin-exacerbated respiratory disease; lysophosphatidic acid can stimulate cell proliferation, and aberrant LPA-signaling has been linked to cancer in numerous ways. Studies of bioactive lipids have helped us to understand more about the formation of thrombosis in cardiovascular disease. And this can help to treat cardiovascular diseases by promoting or inhibiting these active lipids.

References:

  1. Funk, Colin D. Prostaglandins and Leukotrienes: Advances in Eicosanoid Biology. Science. 2001, 294 (5548): 1871–1875.
  2. Gross S, et al. Vascular wall-produced prostaglandin E2 exacerbates arterial thrombosis and atherothrombosis through platelet EP3 receptors. Journal of Experimental Medicine. 2007, 204 (2): 311–320.
  3. Katagiri H. Role of thromboxane derived from COX-1 and -2 in hepatic microcirculatory dysfunction during endotoxemia in mice. Hepatology. 2004, 39 (1): 139–150.
  4. O Byrne, et al. Antileukotrienes in the treatment of asthma. Annals of Internal Medicine. 1997, 127 (6): 472–80.
  5. Sattler K, Levkau B. Sphingosine-1-phosphate as a mediator of high-density lipoprotein effects in cardiovascular protection. Cardiovascular Research. 2009, 82 (2): 201–11.
  6. Tantimonaco M, et al. Physical activity and the endocannabinoid system: an overview. Cell. Mol. Life Sci. 2014, 71 (14): 2681–2698.

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