MKP-2 deficiency Alters Bleeding Time and Red Blood Cell Indices in Diet-Induced Obesity in Mice
Main Article Content
Abstract
Red blood cell dysfunction is linked to overnutrition, which is characterized by inflammation, platelet aggregation and hypercoagulability. Although the role of MAPK in platelets is well established, little is known about the connection between MKPs and red blood cell. We investigated the pathophysiological effects of MKP-2 deletion on bleeding tendencies in platelet counts, and red blood cell indices that are brought on by high-fat diet. In this study, we demonstrated that female Mkp-2-/- mice bleeding times were significantly shortened when they were fed chow diet. Male Mkp-2-/- mice on a high-fat diet show resistance to diet-obesity, which is linked to a shorter bleeding time. In high-fat diet-fed male Mkp-2-/- mice, we observed decreased levels of red blood cells, hemoglobin, and hematocrit. These data suggest that the anemia in these mice may be due to inflammation induced by obesity. When male Mkp-2-/- mice were compared to wild-type controls, their platelet counts were normal; however, the platelets derived from these mice showed increased activation of p38 MAPK and ERK and SDF-1 expression. All of these studies point to a new function for MKP-2 in red blood cell physiology and hemostasis, which may have consequences for thrombotic and hemostatic diseases.
Keywords:
Mitogen-activated protein kinase, Protein tyrosine phosphatase, obesity, red blood cells, platelets, hemostasis
Article Details
How to Cite
SECUNDA, Cassandra et al.
MKP-2 deficiency Alters Bleeding Time and Red Blood Cell Indices in Diet-Induced Obesity in Mice.
Medical Research Archives, [S.l.], v. 11, n. 12, jan. 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/5032>. Date accessed: 15 may 2024.
doi: https://doi.org/10.18103/mra.v11i12.5032.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Arroyo-Johnson, C. and K.D. Mincey, Obesity Epidemiology Worldwide. Gastroenterol Clin North Am, 2016. 45(4): p. 571-579.
2. Andolfi, C. and P.M. Fisichella, Epidemiology of Obesity and Associated Comorbidities. J Laparoendosc Adv Surg Tech A, 2018. 28(8): p. 919-924.
3. Lawan, A. and A.M. Bennett, Mitogen-Activated Protein Kinase Regulation in Hepatic Metabolism. Trends Endocrinol Metab, 2017. 28(12): p. 868-878.
4. Beyerlein, A., et al., Risk factors for obesity: further evidence for stronger effects on overweight children and adolescents compared to normal-weight subjects. PLoS One, 2011. 6(1): p. e15739.
5. Davì, G., et al., Platelet activation in obese women: role of inflammation and oxidant stress. JAMA, 2002. 288(16): p. 2008-14.
6. Simeone, P., et al., Thromboxane-Dependent Platelet Activation in Obese Subjects with Prediabetes or Early Type 2 Diabetes: Effects of Liraglutide- or Lifestyle Changes-Induced Weight Loss. Nutrients, 2018. 10(12).
7. Mkandla, Z., et al., Impaired Glucose Tolerance is Associated with Enhanced Platelet-Monocyte Aggregation in Short-Term High-Fat Diet-Fed Mice. Nutrients, 2019. 11(11).
8. Gehart, H., et al., MAPK signalling in cellular metabolism: stress or wellness? EMBO Rep, 2010. 11(11): p. 834-40.
9. Du, V.X., et al., New insights into the role of erythrocytes in thrombus formation. Semin Thromb Hemost, 2014. 40(1): p. 72-80.
10. Unruh, D., et al., Red Blood Cell Dysfunction Induced by High-Fat Diet: Potential Implications for Obesity-Related Atherosclerosis. Circulation, 2015. 132(20): p. 1898-908.
11. Randi, M.L., et al., Thrombosis and hemorrhage in thrombocytosis: evaluation of a large cohort of patients (357 cases). J Med, 1991. 22(4-5): p. 213-23.
12. Stewart, G.W., et al., Thrombo-embolic disease after splenectomy for hereditary stomatocytosis. Br J Haematol, 1996. 93(2): p. 303-10.
13. Tokarev, A.A., A.A. Butylin, and F.I. Ataullakhanov, Platelet adhesion from shear blood flow is controlled by near-wall rebounding collisions with erythrocytes. Biophys J, 2011. 100(4): p. 799-808.
14. Schreijer, A.J., P.H. Reitsma, and S.C. Cannegieter, High hematocrit as a risk factor for venous thrombosis. Cause or innocent bystander? Haematologica, 2010. 95(2): p. 182-4.
15. Klatt, C., et al., Platelet-RBC interaction mediated by FasL/FasR induces procoagulant activity important for thrombosis. J Clin Invest, 2018. 128(9): p. 3906-3925.
16. Fuentes, E., S. Wehinger, and A. Trostchansky, Regulation of Key Antiplatelet Pathways by Bioactive Compounds with Minimal Bleeding Risk. Int J Mol Sci, 2021. 22(22).
17. Patel, P. and U.P. Naik, Platelet MAPKs-a 20+ year history: What do we really know? J Thromb Haemost, 2020. 18(9): p. 2087-2102.
18. Flaumenhaft, R., Stressed platelets ASK1 for a MAPK. Blood, 2017. 129(9): p. 1066-1068.
19. Mazharian, A., et al., Differential Involvement of ERK2 and p38 in platelet adhesion to collagen. J Biol Chem, 2005. 280(28): p. 26002-10.
20. Canobbio, I., et al., A role for p38 MAP kinase in platelet activation by von Willebrand factor. Thromb Haemost, 2004. 91(1): p. 102-10.
21. Litvinov, R.I. and J.W. Weisel, Role of red blood cells in haemostasis and thrombosis. ISBT Sci Ser, 2017. 12(1): p. 176-183.
22. Hathcock, J.J., Flow effects on coagulation and thrombosis. Arterioscler Thromb Vasc Biol, 2006. 26(8): p. 1729-37.
23. Cheng, H.L., et al., The relationship between obesity and hypoferraemia in adults: a systematic review. Obes Rev, 2012. 13(2): p. 150-61.
24. Armstead, W.M., et al., RBC-coupled tPA Prevents Whereas tPA Aggravates JNK MAPK-Mediated Impairment of ATP- and Ca-Sensitive K Channel-Mediated Cerebrovasodilation After Cerebral Photothrombosis. Transl Stroke Res, 2012. 3(1): p. 114-21.
25. Lawan, A., et al., Hepatic mitogen-activated protein kinase phosphatase 1 selectively regulates glucose metabolism and energy homeostasis. Mol Cell Biol, 2015. 35(1): p. 26-40.
26. Al-Mutairi, M.S., et al., MAP kinase phosphatase-2 plays a critical role in response to infection by Leishmania mexicana. PLoS Pathog, 2010. 6(11): p. e1001192.
27. Lawan, A., et al., Deletion of the dual specific phosphatase-4 (DUSP-4) gene reveals an essential non-redundant role for MAP kinase phosphatase-2 (MKP-2) in proliferation and cell survival. J Biol Chem, 2011. 286(15): p. 12933-43.
28. Fernando, S., et al., Metabolic Impact of MKP-2 Upregulation in Obesity Promotes Insulin Resistance and Fatty Liver Disease. Nutrients, 2022. 14(12).
29. Purdy, J.C. and J.J. Shatzel, The hematologic consequences of obesity. Eur J Haematol, 2021. 106(3): p. 306-319.
30. Chung, D.W., et al., High-density lipoprotein modulates thrombosis by preventing von Willebrand factor self-association and subsequent platelet adhesion. Blood, 2016. 127(5): p. 637-45.
31. Vita, J.A., Endothelial function. Circulation, 2011. 124(25): p. e906-12.
32. Davis, N., S. Katz, and J. Wylie-Rosett, The effect of diet on endothelial function. Cardiol Rev, 2007. 15(2): p. 62-6.
33. Farhangi, M.A., et al., White blood cell count in women: relation to inflammatory biomarkers, haematological profiles, visceral adiposity, and other cardiovascular risk factors. J Health Popul Nutr, 2013. 31(1): p. 58-64.
34. Aigner, E., A. Feldman, and C. Datz, Obesity as an emerging risk factor for iron deficiency. Nutrients, 2014. 6(9): p. 3587-600.
35. Niswander, L.M., et al., SDF-1 dynamically mediates megakaryocyte niche occupancy and thrombopoiesis at steady state and following radiation injury. Blood, 2014. 124(2): p. 277-86.
36. Lawan, A., et al., MKP-2: out of the DUSP-bin and back into the limelight. Biochem Soc Trans, 2012. 40(1): p. 235-9.
37. Naik, M.U., et al., Ask1 regulates murine platelet granule secretion, thromboxane A. Blood, 2017. 129(9): p. 1197-1209.
38. Shi, P., et al., Platelet-Specific p38α Deficiency Improved Cardiac Function After Myocardial Infarction in Mice. Arterioscler Thromb Vasc Biol, 2017. 37(12): p. e185-e196.
2. Andolfi, C. and P.M. Fisichella, Epidemiology of Obesity and Associated Comorbidities. J Laparoendosc Adv Surg Tech A, 2018. 28(8): p. 919-924.
3. Lawan, A. and A.M. Bennett, Mitogen-Activated Protein Kinase Regulation in Hepatic Metabolism. Trends Endocrinol Metab, 2017. 28(12): p. 868-878.
4. Beyerlein, A., et al., Risk factors for obesity: further evidence for stronger effects on overweight children and adolescents compared to normal-weight subjects. PLoS One, 2011. 6(1): p. e15739.
5. Davì, G., et al., Platelet activation in obese women: role of inflammation and oxidant stress. JAMA, 2002. 288(16): p. 2008-14.
6. Simeone, P., et al., Thromboxane-Dependent Platelet Activation in Obese Subjects with Prediabetes or Early Type 2 Diabetes: Effects of Liraglutide- or Lifestyle Changes-Induced Weight Loss. Nutrients, 2018. 10(12).
7. Mkandla, Z., et al., Impaired Glucose Tolerance is Associated with Enhanced Platelet-Monocyte Aggregation in Short-Term High-Fat Diet-Fed Mice. Nutrients, 2019. 11(11).
8. Gehart, H., et al., MAPK signalling in cellular metabolism: stress or wellness? EMBO Rep, 2010. 11(11): p. 834-40.
9. Du, V.X., et al., New insights into the role of erythrocytes in thrombus formation. Semin Thromb Hemost, 2014. 40(1): p. 72-80.
10. Unruh, D., et al., Red Blood Cell Dysfunction Induced by High-Fat Diet: Potential Implications for Obesity-Related Atherosclerosis. Circulation, 2015. 132(20): p. 1898-908.
11. Randi, M.L., et al., Thrombosis and hemorrhage in thrombocytosis: evaluation of a large cohort of patients (357 cases). J Med, 1991. 22(4-5): p. 213-23.
12. Stewart, G.W., et al., Thrombo-embolic disease after splenectomy for hereditary stomatocytosis. Br J Haematol, 1996. 93(2): p. 303-10.
13. Tokarev, A.A., A.A. Butylin, and F.I. Ataullakhanov, Platelet adhesion from shear blood flow is controlled by near-wall rebounding collisions with erythrocytes. Biophys J, 2011. 100(4): p. 799-808.
14. Schreijer, A.J., P.H. Reitsma, and S.C. Cannegieter, High hematocrit as a risk factor for venous thrombosis. Cause or innocent bystander? Haematologica, 2010. 95(2): p. 182-4.
15. Klatt, C., et al., Platelet-RBC interaction mediated by FasL/FasR induces procoagulant activity important for thrombosis. J Clin Invest, 2018. 128(9): p. 3906-3925.
16. Fuentes, E., S. Wehinger, and A. Trostchansky, Regulation of Key Antiplatelet Pathways by Bioactive Compounds with Minimal Bleeding Risk. Int J Mol Sci, 2021. 22(22).
17. Patel, P. and U.P. Naik, Platelet MAPKs-a 20+ year history: What do we really know? J Thromb Haemost, 2020. 18(9): p. 2087-2102.
18. Flaumenhaft, R., Stressed platelets ASK1 for a MAPK. Blood, 2017. 129(9): p. 1066-1068.
19. Mazharian, A., et al., Differential Involvement of ERK2 and p38 in platelet adhesion to collagen. J Biol Chem, 2005. 280(28): p. 26002-10.
20. Canobbio, I., et al., A role for p38 MAP kinase in platelet activation by von Willebrand factor. Thromb Haemost, 2004. 91(1): p. 102-10.
21. Litvinov, R.I. and J.W. Weisel, Role of red blood cells in haemostasis and thrombosis. ISBT Sci Ser, 2017. 12(1): p. 176-183.
22. Hathcock, J.J., Flow effects on coagulation and thrombosis. Arterioscler Thromb Vasc Biol, 2006. 26(8): p. 1729-37.
23. Cheng, H.L., et al., The relationship between obesity and hypoferraemia in adults: a systematic review. Obes Rev, 2012. 13(2): p. 150-61.
24. Armstead, W.M., et al., RBC-coupled tPA Prevents Whereas tPA Aggravates JNK MAPK-Mediated Impairment of ATP- and Ca-Sensitive K Channel-Mediated Cerebrovasodilation After Cerebral Photothrombosis. Transl Stroke Res, 2012. 3(1): p. 114-21.
25. Lawan, A., et al., Hepatic mitogen-activated protein kinase phosphatase 1 selectively regulates glucose metabolism and energy homeostasis. Mol Cell Biol, 2015. 35(1): p. 26-40.
26. Al-Mutairi, M.S., et al., MAP kinase phosphatase-2 plays a critical role in response to infection by Leishmania mexicana. PLoS Pathog, 2010. 6(11): p. e1001192.
27. Lawan, A., et al., Deletion of the dual specific phosphatase-4 (DUSP-4) gene reveals an essential non-redundant role for MAP kinase phosphatase-2 (MKP-2) in proliferation and cell survival. J Biol Chem, 2011. 286(15): p. 12933-43.
28. Fernando, S., et al., Metabolic Impact of MKP-2 Upregulation in Obesity Promotes Insulin Resistance and Fatty Liver Disease. Nutrients, 2022. 14(12).
29. Purdy, J.C. and J.J. Shatzel, The hematologic consequences of obesity. Eur J Haematol, 2021. 106(3): p. 306-319.
30. Chung, D.W., et al., High-density lipoprotein modulates thrombosis by preventing von Willebrand factor self-association and subsequent platelet adhesion. Blood, 2016. 127(5): p. 637-45.
31. Vita, J.A., Endothelial function. Circulation, 2011. 124(25): p. e906-12.
32. Davis, N., S. Katz, and J. Wylie-Rosett, The effect of diet on endothelial function. Cardiol Rev, 2007. 15(2): p. 62-6.
33. Farhangi, M.A., et al., White blood cell count in women: relation to inflammatory biomarkers, haematological profiles, visceral adiposity, and other cardiovascular risk factors. J Health Popul Nutr, 2013. 31(1): p. 58-64.
34. Aigner, E., A. Feldman, and C. Datz, Obesity as an emerging risk factor for iron deficiency. Nutrients, 2014. 6(9): p. 3587-600.
35. Niswander, L.M., et al., SDF-1 dynamically mediates megakaryocyte niche occupancy and thrombopoiesis at steady state and following radiation injury. Blood, 2014. 124(2): p. 277-86.
36. Lawan, A., et al., MKP-2: out of the DUSP-bin and back into the limelight. Biochem Soc Trans, 2012. 40(1): p. 235-9.
37. Naik, M.U., et al., Ask1 regulates murine platelet granule secretion, thromboxane A. Blood, 2017. 129(9): p. 1197-1209.
38. Shi, P., et al., Platelet-Specific p38α Deficiency Improved Cardiac Function After Myocardial Infarction in Mice. Arterioscler Thromb Vasc Biol, 2017. 37(12): p. e185-e196.