Doms № 6 -2022

The management of type 2 diabetes before, during and after Covid Empagliflozin inhibits macrophage inflammation through AMPK signaling pathway and plays an anti-atherosclerosis role-19 infection: what is the evidence?

Jie Fu, Hualin Xu, Fuyun Wu, Qiang Tu, Xiao Dong, Huaqiang Xie, Zheng Cao

Key words: Atherosclerotic, Empagliflozin, p-AMPK, Macrophage, Inflammation.

Abstract
Objective
In recent years, some authoritative clinical studies have found that SGLT2 inhibitorcan reduce cardiovascular risk in patients with diabetes, which may imply that SGLT2 inhibitor can play a role beyond lowering blood glucose. In this study, we explored the effect of empagliflozin on vascular atherosclerosis after removing the effect of diabetes.
Methods
The interaction between SGLT2 inhibitor and the AMPK(Adenosine 5′-monophosphate-activated protein kinase) signal pathway to attenuate atherosclerosis was studied in both spontaneously atherosclerotic mice in vivo and oxidized low-density lipoprotein(ox-LDL) induced macrophage inflammation model in vitro. In vivo experiment the aorta tree and aortic valve area were stained with oil red, and the level of inflammatory factors in the diseased tissue was evaluated by immunohistochemistry. Meanwhile, serum was collected to detect the levels of inflammatory factors. In vitro experiment, the RAW264.7 cell line was selected and ox-LDL was used to induce the release of proinflammatory factors, and different doses of empagliflozin were added. The phagocytosis of macrophages to ox-LDL density lipoprotein, and the expression of inflammatory factors at the protein and RNA levels were measured.
Results
Empagliflozin reduced the area of atherosclerotic plaque and macrophage infiltration in atherosclerotic plaques, decreased the expression of inflammatory factors in local plaque tissues and serum of APOE−/− mice fed with high-fat diet. Empagliflozin can improve the protein expression level of p-AMPK affected by ox-LDL in cell and reduce the gene expression level of inflammatory factors and protein expression level of NF-κB, thus playing an anti-atherosclerosis role.
Conclusions
Empagliflozin improves energy metabolism and reduces the expression of inflammatory factors by activating AMPK. As empagliflozin inhibits atherosclerosis progression, it may be of use in prevention of cardiovascular diseases.

References

  1. Libby, J.E. Buring, L. Badimon, G.K. Hansson, J. Deanfield, M.S. Bittencourt, L. Tokgozoglu, E.F. Lewis, Atherosclerosis, Nat. Rev. Dis. Primers 5 (1) (2019) 56.
  2. K. Arnett, R.S. Blumenthal, M.A. Albert, A.B. Buroker, Z.D. Goldberger, E. J. Hahn, C.D. Himmelfarb, A. Khera, D. Lloyd-Jones, J.W. McEvoy, E.D. Michos, M. D. Miedema, D. Munoz, S.C. Smith Jr., S.S. Virani, K.A. Williams Jr., J. Ye- boah, B. Ziaeian, 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines, J. Am. Coll. Cardiol. 74 (10) (2019) e177–e232.
  3. Collins, C. Reith, J. Emberson, J. Armitage, C. Baigent, L. Blackwell, R. Blumenthal, J. Danesh, G.D. Smith, D. DeMets, S. Evans, M. Law, S. MacMahon, S. Martin, B. Neal, N. Poulter, D. Preiss, P. Ridker, I. Roberts, A. Rodgers, P. Sandercock, K. Schulz, P. Sever, J. Simes, L. Smeeth, N. Wald, S. Yusuf, R. Peto, Interpretation of the evidence for the efficacy and safety of statin therapy, Lancet 388 (10059) (2016) 2532–2561.
  4. Kraft, A. Kahn, J.L. Medina-Franco, M.L. Orlowski, C. Baynes, F. Lopez-Vallejo, K. Barnard, G.M. Maggiora, L.L. Restifo, A cell-based fascin bioassay identifies compounds with potential anti-metastasis or cognition-enhancing functions, Dis. Model. Mech. 6 (1) (2013) 217–235.
  5. Libby, J. Loscalzo, P.M. Ridker, M.E. Farkouh, P.Y. Hsue, V. Fuster, A.A. Hasan, S. Amar, Inflammation, immunity, and infection in atherothrombosis: JACC review topic of the week, J. Am. Coll. Cardiol. 72 (17) (2018) 2071–2081.
  6. J. Moore, S. Koplev, E.A. Fisher, I. Tabas, J.L.M. Bjorkegren, A.C. Doran, J. C. Kovacic, Macrophage trafficking, inflammatory resolution, and genomics in atherosclerosis: JACC macrophage in CVD series (part 2), J. Am. Coll. Cardiol. 72 (18) (2018) 2181–2197.
  7. W. Williams, C. Giannarelli, A. Rahman, G.J. Randolph, J.C. Kovacic, Macrophage biology, classification, and phenotype in cardiovascular disease, J. Am. Coll. Cardiol. 72 (18) (2018) 2166–2180.
  8. Zinman, C. Wanner, J.M. Lachin, D. Fitchett, E. Bluhm- ki, S. Hantel, M. Mattheus, T. Devins, O.E. Johansen, H.J. Woerle, U.C. Broedl, S.E. Inzucchi, E.-R. O. Investigators, Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes, N. Engl. J. Med. 373 (22) (2015) 2117–2128.
  9. Packer, SGLT2 inhibitors produce cardiorenal benefits by promoting adaptive cellular reprogramming to induce a state of fasting mimicry: a paradigm shift in understanding their mechanism of action, Diabetes Care 43 (3) (2020) 508–511.
  10. Lu, X. Li, J. Liu, X. Sun, T. Rousselle, D. Ren, N. Tong, J. Li, AMPK is associated with the beneficial effects of antidiabetic agents on cardiovascular diseases, Biosci. Rep. 39 (2) (2019).
  11. R. Steinberg, J.D. Schertzer, AMPK promotes macrophage fatty acid oxidative metabolism to mitigate inflammation: implications for diabetes and cardiovascular disease, Immunol. Cell Biol. 92 (4) (2014) 340–345.
  12. Yang, B.B. Kahn, H. Shi, B.Z. Xue, Macrophage alpha1 AMP-activated protein kinase (alpha1AMPK) antagonizes fatty acid-induced inflammation through SIRT1, J. Biol. Chem. 285 (25) (2010) 19051–19059.
  13. R. Cowie, M. Fisher, SGLT2 inhibitors: mechanisms of cardiovascular benefit beyond glycaemic control, Nat. Rev. Cardiol. 17 (12) (2020) 761–772.
  14. Soehnlein, P. Libby, Targeting inflammation in atherosclerosis – from experimental insights to the clinic, Nat. Rev. Drug Discov. (2021).
  15. K. Shah, Inflammation, infection and atherosclerosis, Trends. Cardiovasc. Med. 29 (8) (2019) 468–472.
  16. Gistera, G. K. Hansson, The immunology of atherosclerosis, Nat. Rev. Nephrol. 13 (6) (2017) 368–380.
  17. N. Siti, Y. Kamisah, J. Kamsiah, The role of oxidative stress, antioxidants and vascular inflammation in cardiovascular disease (a review), Vasc. Pharmacol. 71 (2015) 40–56.
  18. Zheng, T. Wu, C. Zeng, X. Li, X. Li, D. Wen, T. Ji, T. Lan, L. Xing, J. Li, X. He, L. Wang, SAP deficiency mitigated atherosclerotic lesions in ApoE(–/–) mice, Atherosclerosis 244 (2016) 179–187.
  19. Hoseini, F. Sepahvand, B. Rashidi, A. Sahebkar, A. Masoudifar, H. Mirzaei, NLRP3 inflammasome: its regulation and involvement in atherosclerosis, J. Cell. Physiol. 233 (3) (2018) 2116–2132.
  20. Cochain, E. Vafadarnejad, P. Arampatzi, J. Pelisek, H. Winkels, K. Ley, D. Wolf, A.E. Saliba, A. Zernecke, Single-cell RNA-Seq reveals the transcriptional landscape and heterogeneity of aortic macrophages in murine atherosclerosis, Circ. Res. 122 (12) (2018) 1661–1674.
  21. Iannantuoni, M.M. de Aranzazu, N. Diaz-Morales, R. Falcon, C. Banuls, Z. Abad- Jimenez, V.M. Victor, A. Hernandez- Mijares, S. Rovira-Llopis, The SGLT2 inhibitor Empagliflozin ameliorates the inflammatory profile in type 2 diabetic patients and promotes an antioxidant response in leukocytes, J. Clin. Med. 8 (11) (2019).
  22. Andreadou, P. Efentakis, E. Balafas, G. Togliatto, C.H. Davos, A. Varela, C. A. Dimitriou, P.E. Nikolaou, E. Maratou, V. Lambadiari, I. Ikonomidis, N. Kostomitsopoulos, M.F. Brizzi, G. Dimitriadis, E.K. Iliodromitis, Empagliflozin limits myocardial infarction in vivo and cell death in vitro: role of STAT3, mitochondria, and redox aspects, Front. Physiol. 8 (2017) 1077.
  23. H.Han,T.J.Oh,G.Lee,H.J.Maeng,D.H.Lee,K.M.Kim, S. H. Choi, H. C. Jang, H. S. Lee, K. S. Park, Y. B. Kim, S. Lim, The beneficial effects of empagliflozin, an SGLT2 inhibitor, on atherosclerosis in ApoE (–/–) mice fed a western diet, Diabetologia 60 (2) (2017) 364–376.
  24. N. Koyani, I. Plastira, H. Sourij, S. Hallstrom, A. Schmidt, P. P. Rainer, H. Bugger, S. Frank, E. Malle, D. von Lewinski, Empagliflozin protects heart from inflammation and energy depletion via AMPK activation, Pharmacol. Res. 158 (2020), 104870.
  25. Yanai, H. Katsuyama, H. Hamasaki, H. Adachi, S. Moriyama, R. Yoshikawa, A. Sako, Sodium-glucose cotransporter 2 inhibitors: possible anti-atherosclerotic effects beyond glucose lowering, J. Clin. Med. Res. 8 (1) (2016) 10–14.
  26. Jansen, M. Kvandova, A. Daiber, P. Stamm, K. Frenis, E. Schulz, T. Munzel, S. Kroller-Schon, The AMP-activated protein kinase plays a role in antioxidant defense and regulation of vascular inflammation, Antioxidants (Basel) 9 (6) (2020).
  27. Jiang, H. Du, X. Liu, X. Fu, X. Li, Q. Cao, Artemisinin alleviates atherosclerotic lesion by reducing macrophage inflammation via regulation of AMPK/NF-kappaB/ NLRP3 inflammasomes pathway, J. Drug Target. 28 (1) (2020) 70–79.
  28. W. Jeong, K.C. Hsu, J.W. Lee, M. Ham, J.Y. Huh, H.J. Shin, W.S. Kim, J.B. Kim, Berberine suppresses proinflammatory responses through AMPK activation in macrophages, Am. J. Physiol. Endocrinol. Metab. 296 (4) (2009) E955–E964.

G. Ji, Y. Zhang, Q. Yang, S. Cheng, J. Hao, X. Zhao, Z. Jiang, Genistein suppresses LPS-induced inflammatory response through inhibiting NF-kappaB following AMP kinase activation in RAW 264.7 macrophages, PLoS One 7 (12) (2012), e53101.