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Calcium/calmodulin-dependent protein kinase IV regulates vascular autophagy and insulin signaling through Akt/mTOR/CREB pathway in ob/ob mice

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Abstract

Calcium/calmodulin-dependent protein kinase IV (CaMKIV) has recently emerged as an important regulator of glucose metabolism and vascular function, but the underlying mechanism is not fully understood. Recently, we revealed that CaMKIV limits metabolic disorder and liver insulin resistance and regulates autophagy in high-fat diet-induced obese mice. In the present study, we demonstrated that CaMKIV was not only associated with improvement of glucose tolerance and insulin sensitivity in ob/ob mice but also involved in the regulation of vascular autophagy and mitochondrial biogenesis. Our in vitro data indicated that CaMKIV reversed autophagic imbalance and restored insulin sensitivity in palmitate-induced A7r5 cells with insulin resistance. However, the protective effects of CaMKIV were nullified by suppression of Akt, mTOR, or CREB, suggesting that CaMKIV inhibits autophagy and improves insulin signaling in insulin resistance cell models in an Akt/mTOR/CREB-dependent manner. CaMKIV reversed autophagic imbalance and insulin sensitivity in vascular tissues and vascular cells through Akt/mTOR/CREB signaling, which could be regarded as a novel opportunity for the treatment of insulin resistance.

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Abbreviations

Akt:

Protein kinase B

Atg7:

Autophagy-related 7

BP:

Blood pressure

CaMKIV:

Calcium/calmodulin-dependent protein kinase IV

CaMK:

Ca2+/calmodulin-dependent protein kinase

CREB:

Cyclic AMP response element-binding protein

CVDs:

Cardiovascular diseases

ERs:

Endoplasmic reticulum stress

FBXW7:

F-box and WD repeat domain-containing 7

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

GLUT4:

Isotype 4 of the glucose transporter

GSK-3β:

Glycogen synthase kinase 3β

GTT:

Glucose tolerance test

HFD:

High-fat diet

IgG:

Immunoglobulin G

IL-6:

Interleukin-6

IRS:

Insulin receptor substrate

ITT:

Insulin tolerance test

LC3:

Microtubule-associated protein 1 light chain 3

MCP-1:

Monocyte chemoattractant protein-1

Mfn1:

Mitofusin 1

Mfn2:

Mitofusin 2

mTOR:

Mammalian target of rapamycin

p:

Phosphorylated

NRF-1:

Nuclear respiratory factor 1

PCR:

Polymerase chain reaction

PGC-1α:

Peroxisome proliferator-activated receptor γ coactivator-1α

siRNA:

Small interfering RNA

SIRT1:

Silent mating-type information regulation 2 homolog 1

TFAM:

Mitochondrial transcription factor A

VSMCs:

Vascular smooth muscle cells

References

  1. Chava KR, Karpurapu M, Wang D, Bhanoori M, Kundumani-Sridharan V, Zhang Q, Ichiki T, Glasgow WC, Rao GN (2009) CREB-mediated IL-6 expression is required for 15 (S)-hydroxyeicosatetraenoic acid–induced vascular smooth muscle cell migration. Arterioscler Thromb Vasc Biol 29:809–815

    Article  CAS  Google Scholar 

  2. Chen K, Yu X, Murao K, Imachi H, Li J, Muraoka T, Masugata H, Zhang GX, Kobayashi R, Ishida T, Tokumitsu H (2011) Exendin-4 regulates GLUT2 expression via the CaMKK/CaMKIV pathway in a pancreatic beta-cell line. Metabolism 60:579–585. https://doi.org/10.1016/j.metabol.2010.06.002

    Article  CAS  PubMed  Google Scholar 

  3. Chin ER (2004) The role of calcium and calcium/calmodulin-dependent kinases in skeletal muscle plasticity and mitochondrial biogenesis. Proc Nutr Soc 63:279–286. https://doi.org/10.1079/PNS2004335

    Article  CAS  PubMed  Google Scholar 

  4. Chin ER (2004) The role of calcium and calcium/calmodulin-dependent kinases in skeletal muscle plasticity and mitochondrial biogenesis. Proc Nutr Soc 63:279–286

    Article  CAS  Google Scholar 

  5. Cipolletta E, Monaco S, Maione A, Vitiello L, Campiglia P, Pastore L, Franchini C, Novellino E, Limongelli V, Bayer K (2010) Calmodulin-dependent kinase II mediates vascular smooth muscle cell proliferation and is potentiated by extracellular signal regulated kinase. Endocrinology 151:2747–2759

    Article  CAS  Google Scholar 

  6. Davignon J, Ganz P (2004) Role of endothelial dysfunction in atherosclerosis. Circulation 109:27–32

    Google Scholar 

  7. Ding M-L, Ma H, Man Y-G, Lv H-Y (2017) Protective effects of a green tea polyphenol, epigallocatechin-3-gallate, against sevoflurane-induced neuronal apoptosis involve regulation of CREB/BDNF/TrkB and PI3K/Akt/mTOR signalling pathways in neonatal mice. Can J Physiol Pharmacol 95:1396–1405

    Article  CAS  Google Scholar 

  8. J Evankovich S Cho J Cardinal R Dhupar J Klune M Rosengart D Geller A Tsung 2010 Calcium/calmodulin protein kinase iv prevents high mobility group box protein 1 release during hepatic ischemia/reperfusion injury through regulation of histone deacetylase 1 158 350

  9. Gonzalez CD, Lee MS, Marchetti P, Pietropaolo M, Towns R, Vaccaro MI, Watada H, Wiley JW (2011) The emerging role of autophagy in the pathophysiology of diabetes mellitus. Autophagy 7:2–11. https://doi.org/10.4161/auto.7.1.13044

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Guerfali I, Manissolle C, Durieux A-C, Bonnefoy R, Bartegi A, Freyssenet D (2007) Calcineurin A and CaMKIV transactivate PGC-1α promoter, but differentially regulate cytochrome c promoter in rat skeletal muscle. Pflugers Arch 454:297–305

    Article  CAS  Google Scholar 

  11. Iantorno M, Campia U, Di Daniele N, Nistico S, Forleo GB, Cardillo C, Tesauro M (2014) Obesity, inflammation and endothelial dysfunction. J Biol Regul Homeost Agents 28:169–176

    CAS  PubMed  Google Scholar 

  12. Janus A, Szahidewicz-Krupska E, Mazur G, Doroszko A (2016) Insulin resistance and endothelial dysfunction constitute a common therapeutic target in cardiometabolic disorders. Mediators Inflamm 2016:3634948. https://doi.org/10.1155/2016/3634948

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Jia G, Cheng G, Gangahar DM, Agrawal DK (2006) Insulin-like growth factor-1 and TNF-α regulate autophagy through c-jun N-terminal kinase and Akt pathways in human atherosclerotic vascular smooth cells. Immunol Cell Biol 84:448–454

    Article  CAS  Google Scholar 

  14. Kang C, Ji LL (2012) Role of PGC-1α signaling in skeletal muscle health and disease. Ann N Y Acad Sci 1271:110

    Article  CAS  Google Scholar 

  15. Kim J-a, Wei Y, Sowers JR (2008) Role of mitochondrial dysfunction in insulin resistance. Circ Res 102:401–414

    Article  CAS  Google Scholar 

  16. Krebs J (1998) Calmodulin-dependent protein kinase IV: regulation of function and expression. Biochim Biophys Acta (BBA)-Molecular Cell Research 1448:183–189

    Article  CAS  Google Scholar 

  17. Kudryavtseva O, Aalkjær C, Matchkov VV (2013) Vascular smooth muscle cell phenotype is defined by C a2+-dependent transcription factors. FEBS J 280:5488–5499

    Article  CAS  Google Scholar 

  18. Lerman A, Zeiher AM (2005) Endothelial function: cardiac events. Circulation 111:363–368

    Article  Google Scholar 

  19. Li H, Zhou B, Xu L, Liu J, Zang W, Wu S, Sun H (2014) The reciprocal interaction between autophagic dysfunction and ER stress in adipose insulin resistance. Cell Cycle 13:565–579

    Article  Google Scholar 

  20. Liu J, Li Y, Zhou X, Zhang X, Meng H, Liu S, Zhang L, He J, He Q, Geng Y (2019) CaMKIV limits metabolic damage through induction of hepatic autophagy by CREB in obese mice. J Endocrinol. https://doi.org/10.1530/JOE-19-0251

    Article  PubMed  PubMed Central  Google Scholar 

  21. Maier LS, Bers DM (2007) Role of Ca2+/calmodulin-dependent protein kinase (CaMK) in excitation–contraction coupling in the heart. Cardiovasc Res 73:631–640

    Article  CAS  Google Scholar 

  22. Mollova MY, Katus HA, Backs J (2015) Regulation of CaMKII signaling in cardiovascular disease. Front Pharmacol 6:178

    Article  Google Scholar 

  23. Persaud SJ, Liu B, Sampaio HB, Jones PM, Muller DS (2011) Calcium/calmodulin-dependent kinase IV controls glucose-induced Irs2 expression in mouse beta cells via activation of cAMP response element-binding protein. Diabetologia 54:1109–1120. https://doi.org/10.1007/s00125-011-2050-7

    Article  CAS  PubMed  Google Scholar 

  24. Racioppi L, Means AR (2008) Calcium/calmodulin-dependent kinase IV in immune and inflammatory responses: novel routes for an ancient traveller. Trends Immunol 29:600–607

    Article  CAS  Google Scholar 

  25. Razani B, Feng C, Coleman T, Emanuel R, Wen H, Hwang S, Ting JP, Virgin HW, Kastan MB, Semenkovich CF (2012) Autophagy links inflammasomes to atherosclerotic progression. Cell Metab 15:534–544

    Article  CAS  Google Scholar 

  26. Reusch JE, Watson PA (2004) Loss of CREB regulation of vascular smooth muscle cell quiescence in diabetes. Rev Endocr Metab Disord 5(209):219

    Google Scholar 

  27. MR Rusciano E Sommariva V Douin-Echinard M Ciccarelli P Poggio AS Maione 2019 CaMKII Activity in the inflammatory response of cardiac diseases Int J MolSci 20https://doi.org/10.3390/ijms20184374

  28. Saddouk FZ, Sun LY, Liu YF, Jiang M, Singer DV, Backs J, Van Riper D, Ginnan R, Schwarz JJ, Singer HA (2016) Ca2+/calmodulin-dependent protein kinase II-γ (CaMKIIγ) negatively regulates vascular smooth muscle cell proliferation and vascular remodeling. FASEB J 30:1051–1064

    Article  CAS  Google Scholar 

  29. Santulli G, Cipolletta E, Sorriento D, Del Giudice C, Anastasio A, Monaco S, Maione AS, Condorelli G, Puca A, Trimarco B (2012) CaMK4 gene deletion induces hypertension. J Am Heart Assoc 1:e001081

    Article  Google Scholar 

  30. Sato K, Suematsu A, Nakashima T, Takemoto-Kimura S, Aoki K, Morishita Y, Asahara H, Ohya K, Yamaguchi A, Takai T (2006) Regulation of osteoclast differentiation and function by the CaMK-CREB pathway. Nat Med 12:1410–1416

    Article  CAS  Google Scholar 

  31. Schauer IE, Knaub LA, Lloyd M, Watson PA, Gliwa C, Lewis KE, Chait A, Klemm DJ, Gunter JM, Bouchard R (2010) CREB downregulation in vascular disease: a common response to cardiovascular risk. Arterioscler Thromb Vasc Biol 30:733–741

    Article  CAS  Google Scholar 

  32. Shi D, Gu R, Song Y, Ding M, Huang T, Guo M, Xiao J, Huang W, Liao H (2018) Calcium/calmodulin-dependent protein kinase IV (CaMKIV) mediates acute skeletal muscle inflammatory response. Inflammation 41:199–212

    Article  CAS  Google Scholar 

  33. Spruill TM (2010) Chronic psychosocial stress and hypertension. Curr Hypertens Rep 12:10–16

    Article  Google Scholar 

  34. A Willeford T Suetomi A Nickle HM Hoffman S Miyamoto JH Brown 2018 CaMKIIδ-mediated inflammatory gene expression and inflammasome activation in cardiomyocytes initiate inflammation and induce fibrosis. JCI insight 3

  35. Yu X, Murao K, Sayo Y, Imachi H, Cao WM, Ohtsuka S, Niimi M, Tokumitsu H, Inuzuka H, Wong NC, Kobayashi R, Ishida T (2004) The role of calcium/calmodulin-dependent protein kinase cascade in glucose upregulation of insulin gene expression. Diabetes 53:1475–1481. https://doi.org/10.2337/diabetes.53.6.1475

    Article  CAS  PubMed  Google Scholar 

  36. Zhang X, Howell GM, Guo L, Collage RD, Loughran PA, Zuckerbraun BS, Rosengart MR (2014) CaMKIV-dependent preservation of mTOR expression is required for autophagy during lipopolysaccharide-induced inflammation and acute kidney injury. J Immunol 193:2405–2415. https://doi.org/10.4049/jimmunol.1302798

    Article  CAS  PubMed  Google Scholar 

  37. Zhang X, Howell GM, Guo L, Collage RD, Loughran PA, Zuckerbraun BS, Rosengart MR (2014) CaMKIV-dependent preservation of mTOR expression is required for autophagy during lipopolysaccharide-induced inflammation and acute kidney injury. J Immunol 193:2405–2415

    Article  CAS  Google Scholar 

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Funding

This study was partly supported by funds from the National Natural Science Foundation of China (Program No. 81600619), Natural Science Foundation of Shaanxi Province (No. 708037169021), and the Personal Training Special Fund of the Second Affiliated Hospital of Xi’an Jiaotong University [No. RC (XM) 2016010].

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Authors and Affiliations

  1. Department of Clinical Laboratory, Xi’an Jiaotong University Second Affiliated Hospital, 157 West 5 Road, Xi’an, 710004, Shaanxi, China

    Jiali Liu, Yue Li, Ning Gao, Jing Ji & Qian He

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  1. Jiali Liu
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  2. Yue Li
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  3. Ning Gao
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  4. Jing Ji
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Contributions

LJL and LY processed the samples, analyzed and prepared the data, and were involved in drafting the article. LJL, GN, and JJ contributed to data interpretation and revised the article. LJL and HQ designed the experiments, interpreted the data, and were primary responsible for writing the manuscript. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Qian He.

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Ethics approval

All animal studies were approved by the Xi’an Jiaotong University laboratory Animal Administration Committee and performed according to the Xi'an Jiaotong University Guidelines for Animal Experimentation.

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The authors declare no competing interests.

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Key points

• CaMKIV is associated with improved whole-body glucose metabolism in obese mice.

• CaMKIV restores vascular function through inhibition of autophagy in vivo.

• Effect of CaMKIV on vascular function through Akt/mTOR/CREB pathway.

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Liu, J., Li, Y., Gao, N. et al. Calcium/calmodulin-dependent protein kinase IV regulates vascular autophagy and insulin signaling through Akt/mTOR/CREB pathway in ob/ob mice. J Physiol Biochem 78, 199–211 (2022). https://doi.org/10.1007/s13105-021-00853-6

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