Investigation of anti-atherogenic effects of the alpha-tocopherol long-chain metabolites alpha-13-OH and alpha-13-COOH
Final Report Abstract
Cardiovascular diseases and their complications such as myocardial infarction, are an increasing burden in industrialized Western countries. Therefore, finding new prevention and treatment strategies addresses an important medical need. The aim of my DFG funded research project was to prove the following three main hypotheses: (I) Anti-inflammatory and lipid metabolism-regulating properties of tocopherol-related metabolites, α-13’-OH and α-13’-COOH, lead to anti-atherogenic effects in high fat diet (HFD) fed ApoE-/- mice. (II) The tocotrienol-related metabolite garcinoic acid (GA) modulates the inflammatory response in murine macrophages and in HFD fed ApoE-/- mice, and (III) α-TOH exerts anti-oxidative and anti-inflammatory effects and thereby preserves cardiac function after myocardial infarction. To prove hypothesis I, structure- and doses-dependent application of the long-chain metabolites of αtocopherol (α-LCMs), α-13’-OH and α-13’-COOH, of 1 mg/kg body weight once, twice and thrice a week have been tested. Whereas α-13’-COOH showed a trend in decreasing total plaque size and intraplaque lipid composition with weekly application, α-13’-OH did not show an effect, independent from the doses applied. To further elucidate the effect of α-13’-COOH compared to α-TOH on the formation of unstable plaques which are prone to rupture, the unique tandem stenosis model has been used. α-13’-COOH changed in trend lipid composition within the plaque, while the plaque size was increased. For this part of my project no consistent anti-atherosclerotic effect of the α-LCMs could be observed. But, it cannot be excluded that different application regimens or animal models could lead to different results. In the hypothesis II part of my project, I aimed to characterize the natural compound GA, which is used in traditional medicine, in regards to its anti-inflammatory potential and therefore its effectivity as an anti-atherosclerotic agent in vivo. For the first time, effects of GA on gene and protein regulation of Cox2 and iNos as well as formation of respective signalling molecules, prostanoids and nitric oxide, were shown. In addition, I was able to show decreased intra-plaque inflammation in GA treated mice compared to control mice. These results are of importance for the characterization of GA. For the evaluation of the hypotheses III, an experimental model of cardiac ischemia-reperfusion injury in male C57BL/6 mice has been used. Application of α-TOH ameliorated infarct size compared to control mice, restored cardiac performance, and prevented pathological changes as assessed by stateof-the-art strain and strain rate measurements post ischemia-reperfusion injury. These cardioprotective effects of α-TOH included decreased infiltration of neutrophils in cardiac tissue as well as an anti-oxidative shift from Ly6Chigh to Ly6Clow monocytes systemically. Further, myeloperoxidase expression and activity were reduced, followed by a reduction of reactive oxygen species and lipid peroxidation markers, phosphatidylcholine (PC) hydroxy-octadecadienoic acid (HODE), PC-(34:2)-9-HODE and PC-(34:2)-13-HODE, within the infarcted tissue. Importantly, the applied dose of α-TOH (5 mg/kg body weight) has been approved by the FDA. Since myocardial infarction is a leading cause of death worldwide, therapeutic approaches for patients suffering from myocardial infarction are highly required. Therefore, we developed a new treatment strategy of α-TOH, which is of high clinical relevance and provides new aspects of vitamin E as an actual treatment (not prevention) of myocardial infarction. Concerning this part, Prof. Peter is considering to conduct a clinical trial in humans.
Publications
- (2019) The vitamin E derivative garcinoic acid from Garcinia kola nut seeds attenuates the inflammatory response. Redox biology 24 101166
Wallert, Maria; Bauer, Julia; Kluge, Stefan; Schmölz, Lisa; Chen, Yung-Chih; Ziegler, Melanie; Searle, Amy K.; Maxones, Alexander; Schubert, Martin; Thürmer, Maria; Pein, Helmut; Koeberle, Andreas; Werz, Oliver; Birringer, Marc; Peter, Karlheinz; Lorkowsk
(See online at https://doi.org/10.1016/j.redox.2019.101166) - Analytical strategies to assess the functional metabolome of vitamin E. J Pharm Biomed Anal 2016; 124:399-412
Torquato P, Ripa O, Giusepponi D, Galarini R, Bartolini D, Wallert M, Pellegrino R, Cruciani G, Lorkowski S, Birringer M, Mazzini F, Galli F
(See online at https://dx.doi.org/10.1016/j.jpba.2016.01.056) - Garcinia kola – African ethno medication with anti-atherosclerotic effects? Free Rad Biol Med 2017; 108; 33
Wallert M, Heise J, Chen Y-C, Kluge S, Schmölz L, Schubert M, Searle AK, Koeberle A, Galli F, Werz O, Birringer O, Lorkowski S, Peter K
(See online at https://doi.org/10.1016/j.freeradbiomed.2017.04.133) - Reviving Vitamin E - Long-chain metabolite of α-tocopherol as a new antiatherogenic treatment? ANZMS and AVBS conference booklet 2017:41
Wallert M, Chen Y-C, Searle AK, Birringer M, Lorkowski S, Peter K
- Boost of vitamin E metabolism as a novel treatment strategy for myocardial infarction. Free Rad Biol Med 2018; 120:25
Wallert M, Ziegler M, Wang X, Maluenda A, Lorkowski S, Peter K
(See online at https://doi.org/10.1016/j.freeradbiomed.2018.04.025) - Long-chain metabolites of vitamin E: metabolic activation as a general concept for lipid-soluble vitamins? Antioxidants 2018; 7(1)
Schubert M, Kluge S, Schmölz L, Wallert M, Galli F, Birringer M, Lorkowski S
(See online at https://doi.org/10.3390/antiox7010010)
