Exercise Regulates the Lactate Receptor HCAR1 and ERK1/2-PI3K/Akt Pathways to Promote Cerebral Angiogenesis
-
Shicun Zhang
,
Fang Wu
,
Lan Zhan
,
Wennan Lin
,
Chunming Liang
,
Yu Pang
,
Jiawen Zhang
,
Zhuang Mu
Abstract
Background: We aimed to explore the ole and mechanism of lactate receptor (HCAR1) in the angiogenesis of leptomeningeal fibroblast-like cells.
Methods: Human brain fibroblast-like cells were selected and some cells were deactivated, analyzed and compared with HCAR1 mRNA and protein expressions in deactivated/normal cells. HCAR1-/- mice and wild type (WT) mice were selected and divided into WT, WT exercise, HCAE1 KO and HCAE1 KO exercise groups, with 10 mice for each group. HCAR1mRNA and expression levels of proteins in fibroblast-like cells, mRNA and expression levels of proteins in Collagen IV, phosphatidylinositol trihydroxykinase (PI3K), serine threonine kinase (AKT) and extracellular signal-regulated kinases 1 and 2 (ERK1/2) in hippocampus were compared, and the microvessel density (MVD) and diameter were calculated.
Results: mRNA and expression levels of proteins in Collagen IV, PI3K, AKT, ERK1/2 and MVD in hippocampus were significantly higher in the WT exercise group than those in the WT group, microvessel diameter was significantly lower than that in the WT group (P<0.05). mRNA and expression levels of proteins in Collagen IV, PI3K, AKT, ERK1/2 and MVD in hippocampus in the HCAR1 KO and HCAR1 KO exercise groups were significantly lower than those in the WT group, microvessel diameter was higher than that in the WT group (P<0.05). Compared with the HCAR1 KO exercise group, the changes of mRNA in Collagen IV, PI3K, AKT, ERK1/2 and microvascular were not significant.
Conclusion: Exercise can promote cerebral angiogenesis through the activation of the lactate receptor HCAR1 and the ERK1/2-PI3K/Akt signaling pathways.
1. Zhang M, Wang Y, Chen X, Dai L, Bai Y, Yao Z, Li R, Guo H (2021). Inhibition of Lactate-GPR81-PI3K/Akt Pathway May Exacerbate Aβ Aggregation in 3-Month-Old APP/PS1 Mice. Research Square, 65(2):1569-1673.
2. Castro IM, Loureiro-Dias MC (2020). Utili-zation of Lactic Acid by Fusarium ox-ysporum var. lini: Regulation of Transport and Metabolism. Appl Environ Microbiol, 60(1):102-105.
3. Roosterman D, Cottrell GS (2020). Astro-cytes and neurons communicate via a monocarboxylic acid shuttle. AIMS Neu-rosci, 7(2):94-106.
4. Zhao Y, Li M, Yao X, Fei Y, Lin Z, Li Z, Cai K, Zhao Y, Luo Z (2020). HCAR1/MCT1 Regulates Tumor Ferrop-tosis through the Lactate-Mediated AMPK-SCD1 Activity and Its Therapeu-tic Implications. Cell Rep, 33(10):108487.
5. Khatib-Massalha E, Bhattacharya S, Mas-salha H, et al (2020). Lactate released by inflammatory bone marrow neutrophils induces their mobilization via endothelial GPR81 signaling. Nat Commun, 11(1):1-5
6. Shan B, Ai Z, Zeng S, et al (2020). Gut mi-crobiome-derived lactate promotes to anxiety-like behaviors through GPR81 re-ceptor-mediated lipid metabolism path-way. Psychoneuroendocrinology, 117(9):104699.
7. Yang K, Xu J, Fan M, Tu F, Wang X, Ha T, Williams DL, Li C (2020). Lactate Sup-presses Macrophage Pro-Inflammatory Response to LPS Stimulation by Inhibi-tion of YAP and NF-κB Activation via GPR81-Mediated Signaling. Front Immunol, 11(6):587913-587913.
8. Laroche S, Stil A, Germain P, Cherif H, Chemtob S, Bouchard JF (2021). Partici-pation of L-Lactate and Its Receptor HCAR1/GPR81 in Neurovisual Devel-opment. Cells, 10(7):1640-1645.
9. Davidsson Ö, Nilsson K, Brånalt J, et al (2020). Identification of novel GPR81 agonist lead series for target biology eval-uation. Bioorg Med Chem Lett, 30(4):126953-126954
10. Schaffenrath J, Wyss T, He L, et al (2021). Blood-brain barrier alterations in human brain tumors revealed by genome-wide transcriptomic profiling. Neuro Oncol, 2021(5):e659-e662.
11. Zheng QL, Wang SL, Bao XQ, et al (2020). The relationship between the plasma cor-tisol,lactic acid and neutrophil capture re-ticulum levels and clinical prognosis in sepsis patients. Chinese Journal of Health Laboratory Technology, 89(9):89-96.
12. Diebold R, Schopf B, Stammer H, Mendling W (2021). Correction to: Vaginal treat-ment with lactic acid gel delays relapses in recurrent urinary tract infections: results from an open, multicentre observational study. Arch Gynecol Obstet, 304(2):1-5.
13. Abdel-Rahman MA, Hassan ED, Alrefaey H, et al (2021). Subsequent improvement of lactic acid production from beet molasses by Enterococcus hirae ds10 using differ-ent fermentation strategies. Bioresource Technology Reports, 13(6):100617.
14. Gang R, Nagarajan SM, Anandhan P (2021). Mechanism of the effect of traditional Chinese medicine fumigation on blood lactic acid in exercise body. Journal of Am-bient Intelligence and Humanized Computing, 12(3):3295-3301.
15. Huang X, Wang W, Zheng X, Zhang X, Wang Z (2020). Magnesium Trisilicate Coated FeO Nanoparticles as Prompt and Efficient Lactic Acid Removers Po-tential for Exercise-Induce Fatigue Pre-vention. J Biomed Nanotechnol, 16(4):531-537.
16. Xie Q, Zhu Z, He Y, et al (2020). Corrigen-dum to "A lactate-induced Snail/STAT3 pathway drives GPR81 expression in lung cancer cells" [Biochim. Biophys. Acta (BBA) - Mol. Basis Dis. 1866 (2020) Arti-cle 165576]. Biochim Biophys Acta Mol Basis Dis, 1867(3):166030.
17. de Castro Abrantes H, Briquet M, Schmuziger C, et al (2019). The Lactate Receptor HCAR1 Modulates Neuronal Network Activity through the Activation of Gα and Gβγ Subunits. J Neurosci, 39(23)4422-4433.
18. Ma J, Han S, Liu X, Zhou Z (2021). Sodium bicarbonated Ringer's solution effectively improves coagulation function and lactic acid metabolism in patients with severe multiple injuries and traumatic shock. Am J Transl Res, 13(5):5043-5050.
19. Ye W, Sun J, Li C, et al (2020). Adenosine A3 Receptor Mediates ERK1/2- and JNK-Dependent TNF-α Production in Toxo-plasma gondii-Infected HTR8/SVneo Human Extravillous Trophoblast Cells. Korean J Parasitol, 58(4):393-402.
20. de Castro Abrantes H, Briquet M, Schmuziger C, et al (2019). The Lactate Receptor HCAR1 Modulates Neuronal Network Activity through the Activation of Galpha and Gbetagamma Subunits. J Neurosci, 39（23）: 4422-4433.
21. Zhang R, Wang YH, Shi X, Ji J, Zhan FQ, Leng H (2021). Sortilin regulates keratino-cyte proliferation and apoptosis through the PI3K-AKT signaling pathway. Life Sci, 278(3):119630.
22. Ma Y, Zhan S, Lu H, et al (2020). B7-H3 regulates KIF15-activated ERK1/2 path-way and contributes to radioresistance in colorectal cancer. Cell Death Dis, 11(10):824-828.
23. Li QY, Yang K, Liu FG, Sun XG, Chen L, Xiu H, Liu XS (2020). Long noncoding RNA CASC2c inhibited cell proliferation in hepatocellular carcinoma by inactivated ERK1/2 and Wnt/β-catenin signaling pathway. Clin Transl Oncol, 22(3):302-310.
24. Luo X, Li Z, Zhao J, Deng Y, Zhong Y, Zhang M (2020). Fyn gene silencing re-duces oligodendrocytes apoptosis through inhibiting ERK1/2 phosphory-lation in epilepsy. Artif Cells Nanomed Bio-technol, 48(1):298-304.
25. Coco M, Buscemi A, Ramaci T, et al (2020). Influences of Blood Lactate Levels on Cognitive Domains and Physical Health during a Sports Stress. Brief Review. Int J Environ Res Public Health, 17(23):9043.
26. Ducrocq GP, Kim JS, Estrada JA, Kaufman MP (2021). ASIC1a plays a key role in evoking the metabolic component of the exercise pressor reflex in rats. Am J Physiol Heart Circ Physiol, 15(4):45-53.
27. Wang M, Gamo NJ, Yang Y, et al (2011). Neuronal basis of age-related working memory decline. Nature, 476（7359）:210-213.
28. De Rossi P, Harde E, Dupuis JP, et al (2016). A critical role for VEGF and VEGFR2 in NMDA receptor synaptic function and fear-related behavior. Mol Psychiatry, 21（12）: 1768-1780.
29. Agnani B, Solanki R, Ansari M, et al (2020). Prognostic Significance of Microvessel Density as Assessed by anti CD34 Mon-oclonal Antibody in Invasive Ductal Car-cinoma of Breast. Asian Pacific Journal of Cancer Biology, 5(3):75-79.
30. Muhammad Sakri MS, Abdul Rahman WFW, Tengku Din TADA, Idris FM, Jaafar H (2020). Microvessel density and vascular endothelial growth factor receptors in breast carcinoma under the influence of rapamycin and platelet factor 4. Indian J Pathol Microbiol, 63(2):205-209.
2. Castro IM, Loureiro-Dias MC (2020). Utili-zation of Lactic Acid by Fusarium ox-ysporum var. lini: Regulation of Transport and Metabolism. Appl Environ Microbiol, 60(1):102-105.
3. Roosterman D, Cottrell GS (2020). Astro-cytes and neurons communicate via a monocarboxylic acid shuttle. AIMS Neu-rosci, 7(2):94-106.
4. Zhao Y, Li M, Yao X, Fei Y, Lin Z, Li Z, Cai K, Zhao Y, Luo Z (2020). HCAR1/MCT1 Regulates Tumor Ferrop-tosis through the Lactate-Mediated AMPK-SCD1 Activity and Its Therapeu-tic Implications. Cell Rep, 33(10):108487.
5. Khatib-Massalha E, Bhattacharya S, Mas-salha H, et al (2020). Lactate released by inflammatory bone marrow neutrophils induces their mobilization via endothelial GPR81 signaling. Nat Commun, 11(1):1-5
6. Shan B, Ai Z, Zeng S, et al (2020). Gut mi-crobiome-derived lactate promotes to anxiety-like behaviors through GPR81 re-ceptor-mediated lipid metabolism path-way. Psychoneuroendocrinology, 117(9):104699.
7. Yang K, Xu J, Fan M, Tu F, Wang X, Ha T, Williams DL, Li C (2020). Lactate Sup-presses Macrophage Pro-Inflammatory Response to LPS Stimulation by Inhibi-tion of YAP and NF-κB Activation via GPR81-Mediated Signaling. Front Immunol, 11(6):587913-587913.
8. Laroche S, Stil A, Germain P, Cherif H, Chemtob S, Bouchard JF (2021). Partici-pation of L-Lactate and Its Receptor HCAR1/GPR81 in Neurovisual Devel-opment. Cells, 10(7):1640-1645.
9. Davidsson Ö, Nilsson K, Brånalt J, et al (2020). Identification of novel GPR81 agonist lead series for target biology eval-uation. Bioorg Med Chem Lett, 30(4):126953-126954
10. Schaffenrath J, Wyss T, He L, et al (2021). Blood-brain barrier alterations in human brain tumors revealed by genome-wide transcriptomic profiling. Neuro Oncol, 2021(5):e659-e662.
11. Zheng QL, Wang SL, Bao XQ, et al (2020). The relationship between the plasma cor-tisol,lactic acid and neutrophil capture re-ticulum levels and clinical prognosis in sepsis patients. Chinese Journal of Health Laboratory Technology, 89(9):89-96.
12. Diebold R, Schopf B, Stammer H, Mendling W (2021). Correction to: Vaginal treat-ment with lactic acid gel delays relapses in recurrent urinary tract infections: results from an open, multicentre observational study. Arch Gynecol Obstet, 304(2):1-5.
13. Abdel-Rahman MA, Hassan ED, Alrefaey H, et al (2021). Subsequent improvement of lactic acid production from beet molasses by Enterococcus hirae ds10 using differ-ent fermentation strategies. Bioresource Technology Reports, 13(6):100617.
14. Gang R, Nagarajan SM, Anandhan P (2021). Mechanism of the effect of traditional Chinese medicine fumigation on blood lactic acid in exercise body. Journal of Am-bient Intelligence and Humanized Computing, 12(3):3295-3301.
15. Huang X, Wang W, Zheng X, Zhang X, Wang Z (2020). Magnesium Trisilicate Coated FeO Nanoparticles as Prompt and Efficient Lactic Acid Removers Po-tential for Exercise-Induce Fatigue Pre-vention. J Biomed Nanotechnol, 16(4):531-537.
16. Xie Q, Zhu Z, He Y, et al (2020). Corrigen-dum to "A lactate-induced Snail/STAT3 pathway drives GPR81 expression in lung cancer cells" [Biochim. Biophys. Acta (BBA) - Mol. Basis Dis. 1866 (2020) Arti-cle 165576]. Biochim Biophys Acta Mol Basis Dis, 1867(3):166030.
17. de Castro Abrantes H, Briquet M, Schmuziger C, et al (2019). The Lactate Receptor HCAR1 Modulates Neuronal Network Activity through the Activation of Gα and Gβγ Subunits. J Neurosci, 39(23)4422-4433.
18. Ma J, Han S, Liu X, Zhou Z (2021). Sodium bicarbonated Ringer's solution effectively improves coagulation function and lactic acid metabolism in patients with severe multiple injuries and traumatic shock. Am J Transl Res, 13(5):5043-5050.
19. Ye W, Sun J, Li C, et al (2020). Adenosine A3 Receptor Mediates ERK1/2- and JNK-Dependent TNF-α Production in Toxo-plasma gondii-Infected HTR8/SVneo Human Extravillous Trophoblast Cells. Korean J Parasitol, 58(4):393-402.
20. de Castro Abrantes H, Briquet M, Schmuziger C, et al (2019). The Lactate Receptor HCAR1 Modulates Neuronal Network Activity through the Activation of Galpha and Gbetagamma Subunits. J Neurosci, 39（23）: 4422-4433.
21. Zhang R, Wang YH, Shi X, Ji J, Zhan FQ, Leng H (2021). Sortilin regulates keratino-cyte proliferation and apoptosis through the PI3K-AKT signaling pathway. Life Sci, 278(3):119630.
22. Ma Y, Zhan S, Lu H, et al (2020). B7-H3 regulates KIF15-activated ERK1/2 path-way and contributes to radioresistance in colorectal cancer. Cell Death Dis, 11(10):824-828.
23. Li QY, Yang K, Liu FG, Sun XG, Chen L, Xiu H, Liu XS (2020). Long noncoding RNA CASC2c inhibited cell proliferation in hepatocellular carcinoma by inactivated ERK1/2 and Wnt/β-catenin signaling pathway. Clin Transl Oncol, 22(3):302-310.
24. Luo X, Li Z, Zhao J, Deng Y, Zhong Y, Zhang M (2020). Fyn gene silencing re-duces oligodendrocytes apoptosis through inhibiting ERK1/2 phosphory-lation in epilepsy. Artif Cells Nanomed Bio-technol, 48(1):298-304.
25. Coco M, Buscemi A, Ramaci T, et al (2020). Influences of Blood Lactate Levels on Cognitive Domains and Physical Health during a Sports Stress. Brief Review. Int J Environ Res Public Health, 17(23):9043.
26. Ducrocq GP, Kim JS, Estrada JA, Kaufman MP (2021). ASIC1a plays a key role in evoking the metabolic component of the exercise pressor reflex in rats. Am J Physiol Heart Circ Physiol, 15(4):45-53.
27. Wang M, Gamo NJ, Yang Y, et al (2011). Neuronal basis of age-related working memory decline. Nature, 476（7359）:210-213.
28. De Rossi P, Harde E, Dupuis JP, et al (2016). A critical role for VEGF and VEGFR2 in NMDA receptor synaptic function and fear-related behavior. Mol Psychiatry, 21（12）: 1768-1780.
29. Agnani B, Solanki R, Ansari M, et al (2020). Prognostic Significance of Microvessel Density as Assessed by anti CD34 Mon-oclonal Antibody in Invasive Ductal Car-cinoma of Breast. Asian Pacific Journal of Cancer Biology, 5(3):75-79.
30. Muhammad Sakri MS, Abdul Rahman WFW, Tengku Din TADA, Idris FM, Jaafar H (2020). Microvessel density and vascular endothelial growth factor receptors in breast carcinoma under the influence of rapamycin and platelet factor 4. Indian J Pathol Microbiol, 63(2):205-209.
| Files | ||
| Issue | Vol 51 No 10 (2022) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijph.v51i10.10988 | |
| Keywords | ||
| HCAR1 protein Fibroblast-like cells Angiogenesis | ||
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How to Cite
1.
Zhang S, Wu F, Zhan L, Lin W, Liang C, Pang Y, Zhang J, Mu Z. Exercise Regulates the Lactate Receptor HCAR1 and ERK1/2-PI3K/Akt Pathways to Promote Cerebral Angiogenesis. Iran J Public Health. 2022;51(10):2298-2307.
