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The role of thrombospondin-1-mediated TGF-β1 on collagen type III synthesis induced by high glucose

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Abstract

Transforming growth factor-β1 (TGF-β1) has been thought to play a major role during cardiac fibrosis in the development of diabetic cardiomyopathy, and cardiac fibrosis mainly as a result of an increase of collagen type III occurs in the human hearts with diabetes. Thrombospondin-1 (TSP-1) has been reported to activate the latent complex of TGF-β1. We examined the effects of TSP-1 on the expression of TGF-β1 and collagen type III by rat cardiac fibroblasts in high ambient glucose. We demonstrated that high glucose induces the mRNA and protein expression of collagen type III, TGF-β1, and TSP-1. Furthermore, the mRNA and protein expression of collagen type III induced by high glucose was downregulated after treatment with TGF-β1 antibody, or TSP-1 siRNA. The expression of TGF-β1 increased by high glucose was also reversed after treatment with TSP-1 siRNA. Our findings suggest that the TSP-1 participates in the upregulation of TGF-β1, collagen type III by high glucose and may provide new therapeutic strategies for diabetic cardiomyopathy.

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Abbreviations

TSP-1:

Thrombospondin-1

TGF-β1:

Transforming growth factor-β1

References

  1. Hunt SA, Baker DW, Chin MH, Cinquegrani MP, Feldman AM, Francis GS, Ganiats TG, Goldstein S, Gregoratos G, Jessup ML, Noble RJ, Packer M, Silver MA, Stevenson LW, Gibbons RJ, Antman EM, Alpert JS, Faxon DP, Fuster V, Jacobs AK, Hiratzka LF, Russell RO, Smith SC, Jr. (2001) Acc/aha guidelines for the evaluation and management of chronic heart failure in the adult. Journal of the American College of Cardiology 38 (7):2101-2113. doi: 10.1161/hc4901.102568

    Article  CAS  PubMed  Google Scholar 

  2. Aneja A, Tang WH, Bansilal S, Garcia MJ, Farkouh ME (2008) Diabetic cardiomyopathy: insights into pathogenesis, diagnostic challenges, and therapeutic options. Am J Med 121(9):748–757. doi:10.1016/j.amjmed.2008.03.046

    Article  PubMed  Google Scholar 

  3. Lago RM, Singh PP, Nesto RW (2007) Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials. Lancet 370(9593):1129–1136. doi:10.1016/S0140-6736(07)61514-1

    Article  CAS  PubMed  Google Scholar 

  4. van Hoeven KH, Factor SM (1990) A comparison of the pathological spectrum of hypertensive, diabetic, and hypertensive-diabetic heart disease. Circulation 82(3):848–855

    PubMed  Google Scholar 

  5. Asbun J, Villarreal FJ (2006) The pathogenesis of myocardial fibrosis in the setting of diabetic cardiomyopathy. J Am Coll Cardiol 47(4):693–700. doi:10.1016/j.jacc.2005.09.050

    Article  CAS  PubMed  Google Scholar 

  6. Suskin N, McKelvie RS, Burns RJ, Latini R, Pericak D, Probstfield J, Rouleau JL, Sigouin C, Solymoss CB, Tsuyuki R, White M, Yusuf S (2000) Glucose and insulin abnormalities relate to functional capacity in patients with congestive heart failure. Eur Heart J 21(16):1368–1375. doi:10.1053/euhj.1999.2043

    Article  CAS  PubMed  Google Scholar 

  7. Tang M, Zhang W, Lin H, Jiang H, Dai H, Zhang Y (2007) High glucose promotes the production of collagen types I and III by cardiac fibroblasts through a pathway dependent on extracellular-signal-regulated kinase 1/2. Mol Cell Biochem 301(1–2):109–114. doi:10.1007/s11010-006-9401-6

    Article  CAS  PubMed  Google Scholar 

  8. Pauschinger M, Knopf D, Petschauer S, Doerner A, Poller W, Schwimmbeck PL, Kuhl U, Schultheiss HP (1999) Dilated cardiomyopathy is associated with significant changes in collagen type I/III ratio. Circulation 99(21):2750–2756. doi:10.1016/0735-1097(94)00557-7

    CAS  PubMed  Google Scholar 

  9. Shimizu M, Umeda K, Sugihara N, Yoshio H, Ino H, Takeda R, Okada Y, Nakanishi I (1993) Collagen remodelling in myocardia of patients with diabetes. J Clin Pathol 46(1):32–36

    Article  CAS  PubMed  Google Scholar 

  10. Mizushige K, Yao L, Noma T, Kiyomoto H, Yu Y, Hosomi N, Ohmori K, Matsuo H (2000) Alteration in left ventricular diastolic filling and accumulation of myocardial collagen at insulin-resistant prediabetic stage of a type II diabetic rat model. Circulation 101(8):899–907

    CAS  PubMed  Google Scholar 

  11. Westermann D, Rutschow S, Jager S, Linderer A, Anker S, Riad A, Unger T, Schultheiss HP, Pauschinger M, Tschope C (2007) Contributions of inflammation and cardiac matrix metalloproteinase activity to cardiac failure in diabetic cardiomyopathy: the role of angiotensin type 1 receptor antagonism. Diabetes 56(3):641–646. doi:10.2337/db06-1163

    Article  CAS  PubMed  Google Scholar 

  12. Lawrence DA (1996) Transforming growth factor-beta: a general review. Eur Cytokine Netw 7(3):363–374

    CAS  PubMed  Google Scholar 

  13. Bujak M, Frangogiannis NG (2007) The role of tgf-beta signaling in myocardial infarction and cardiac remodeling. Cardiovasc Res 74(2):184–195. doi:10.1016/j.cardiores.2006.10.002

    Article  CAS  PubMed  Google Scholar 

  14. Hayashida T, Schnaper HW (2004) High ambient glucose enhances sensitivity to tgf-beta1 via extracellular signal–regulated kinase and protein kinase C delta activities in human mesangial cells. J Am Soc Nephrol 15(8):2032–2041. doi:10.1097/01.ASN.0000133198.74973.60

    Article  CAS  PubMed  Google Scholar 

  15. Lawler J (2002) Thrombospondin-1 as an endogenous inhibitor of angiogenesis and tumor growth. J Cell Mol Med 6(1):1–12. doi:10.1111/j.1582-4934.2002.tb00307.x

    Article  CAS  PubMed  Google Scholar 

  16. Meszaros JG, Gonzalez AM, Endo-Mochizuki Y, Villegas S, Villarreal F, Brunton LL (2000) Identification of g protein-coupled signaling pathways in cardiac fibroblasts: cross talk between g(q) and g(s). Am J Physiol Cell Physiol 278(1):C154–C162

    CAS  PubMed  Google Scholar 

  17. Villarreal FJ, Kim NN, Ungab GD, Printz MP, Dillmann WH (1993) Identification of functional angiotensin ii receptors on rat cardiac fibroblasts. Circulation 88(6):2849–2861

    CAS  PubMed  Google Scholar 

  18. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative pcr and the 2(-delta delta c(t)) method. Methods 25(4):402–408

    Article  CAS  PubMed  Google Scholar 

  19. Han DC, Isono M, Hoffman BB, Ziyadeh FN (1999) High glucose stimulates proliferation and collagen type i synthesis in renal cortical fibroblasts: mediation by autocrine activation of tgf-beta. J Am Soc Nephrol 10(9):1891–1899

    CAS  PubMed  Google Scholar 

  20. Tokudome T, Horio T, Yoshihara F, Suga S, Kawano Y, Kohno M, Kangawa K (2004) Direct effects of high glucose and insulin on protein synthesis in cultured cardiac myocytes and DNA and collagen synthesis in cardiac fibroblasts. Metabolism 53(6):710–715. doi:10.1016/j.metabol.2004.01.006

    Article  CAS  PubMed  Google Scholar 

  21. Wu D, Peng F, Zhang B, Ingram AJ, Kelly DJ, Gilbert RE, Gao B, Krepinsky JC (2009) Pkc-beta1 mediates glucose-induced akt activation and tgf-beta1 upregulation in mesangial cells. J Am Soc Nephrol 20(3):554–566. doi:10.1681/ASN.2008040445

    Article  CAS  PubMed  Google Scholar 

  22. Medcalf JF, Walls J, Pawluczyk IZ, Harris KP (2001) Effects of glucose dialysate on extracellular matrix production by human peritoneal mesothelial cells (hpmc): the role of tgf-beta. Nephrol Dial Transplant 16(9):1885–1892

    Article  CAS  PubMed  Google Scholar 

  23. Lam S, van der Geest RN, Verhagen NA, van Nieuwenhoven FA, Blom IE, Aten J, Goldschmeding R, Daha MR, van Kooten C (2003) Connective tissue growth factor and igf-i are produced by human renal fibroblasts and cooperate in the induction of collagen production by high glucose. Diabetes 52(12):2975–2983. doi:10.2337/diabetes.52.12.2975

    Article  CAS  PubMed  Google Scholar 

  24. Colwell AS, Faudoa R, Krummel TM, Longaker MT, Lorenz HP (2007) Transforming growth factor-beta, smad, and collagen expression patterns in fetal and adult keratinocytes. Plast Reconstr Surg 119:852–857. doi:10.1097/01.prs.0000255541.39993.66

    Article  CAS  PubMed  Google Scholar 

  25. Stratton R, Rajkumar V, Ponticos M, Nichols B, Shiwen X, Black CM, Abraham DJ, Leask A (2002) Prostacyclin derivatives prevent the fibrotic response to tgf-beta by inhibiting the ras/mek/erk pathway. Faseb J 16(14):1949–1951. doi:10.1096/fj.02-0204fje

    CAS  PubMed  Google Scholar 

  26. Schiller M, Dennler S, Anderegg U, Kokot A, Simon JC, Luger TA, Mauviel A, Bohm M (2009) Increased camp levels modulate transforming growth factor(tgf-{beta})/smad-induced expression of extracellular matrix components and other key fibroblast effector functions. J Biol Chem 285(1):409–421. doi:10.1074/jbc.M109.038620

    Article  PubMed  Google Scholar 

  27. Murphy-Ullrich JE, Poczatek M (2000) Activation of latent tgf-beta by thrombospondin-1: mechanisms and physiology. Cytokine Growth Factor Rev 11(1–2):59–69

    Article  CAS  PubMed  Google Scholar 

  28. Bhattacharyya S, Marinic TE, Krukovets I, Hoppe G, Stenina OI (2008) Cell type-specific post-transcriptional regulation of production of the potent antiangiogenic and proatherogenic protein thrombospondin-1 by high glucose. J Biol Chem 283(9):5699–5707. doi:10.1074/jbc.M706435200

    Article  CAS  PubMed  Google Scholar 

  29. Poczatek MH, Hugo C, Darley-Usmar V, Murphy-Ullrich JE (2000) Glucose stimulation of transforming growth factor-beta bioactivity in mesangial cells is mediated by thrombospondin-1. Am J Pathol 157(4):1353–1363

    CAS  PubMed  Google Scholar 

  30. Yung S, Lee CY, Zhang Q, Lau SK, Tsang RC, Chan TM (2006) Elevated glucose induction of thrombospondin-1 up-regulates fibronectin synthesis in proximal renal tubular epithelial cells through tgf-beta1 dependent and tgf-beta1 independent pathways. Nephrol Dial Transplant 21(6):1504–1513. doi:10.1093/ndt/gfl017

    Article  CAS  PubMed  Google Scholar 

  31. Belmadani S, Bernal J, Wei CC, Pallero MA, Dell’italia L, Murphy-Ullrich JE, Berecek KH (2007) A thrombospondin-1 antagonist of transforming growth factor-beta activation blocks cardiomyopathy in rats with diabetes and elevated angiotensin ii. Am J Pathol 171(3):777–789. doi:10.2353/ajpath.2007.070056

    Article  CAS  PubMed  Google Scholar 

  32. Ribeiro SM, Poczatek M, Schultz-Cherry S, Villain M, Murphy-Ullrich JE (1999) The activation sequence of thrombospondin-1 interacts with the latency-associated peptide to regulate activation of latent transforming growth factor-beta. J Biol Chem 274(19):13586–13593. doi:10.1074/jbc.274.19.13586

    Article  CAS  PubMed  Google Scholar 

  33. Schultz-Cherry S, Chen H, Mosher DF, Misenheimer TM, Krutzsch HC, Roberts DD, Murphy-Ullrich JE (1995) Regulation of transforming growth factor-beta activation by discrete sequences of thrombospondin 1. J Biol Chem 270(13):7304–7310. doi:10.1074/jbc.270.13.7304

    Article  CAS  PubMed  Google Scholar 

  34. Ihm SH, Chang K, Kim HY, Baek SH, Youn HJ, Seung KB, Kim JH (2010) Peroxisome proliferator-activated receptor-gamma activation attenuates cardiac fibrosis in type 2 diabetic rats: The effect of rosiglitazone on myocardial expression of receptor for advanced glycation end products and of connective tissue growth factor. Basic Res Cardiol 105(3):399–407. doi:10.1007/s00395-009-0071-x

    Article  CAS  PubMed  Google Scholar 

  35. Wang P, Li HW, Wang YP, Chen H, Zhang P (2009) Effects of recombinant human relaxin upon proliferation of cardiac fibroblast and synthesis of collagen under high glucose condition. J Endocrinol Invest 32(3):242–247

    CAS  PubMed  Google Scholar 

  36. Singh VP, Baker KM, Kumar R (2008) Activation of the intracellular renin-angiotensin system in cardiac fibroblasts by high glucose: role in extracellular matrix production. Am J Physiol Heart Circ Physiol 294(4):H1675–H1684. doi:10.1152/ajpheart.91493.2007

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported by the research grants from Key Technologies R & D Program of Shandong Province (2006GG2202020), the Independent Innovation Foundation of Shandong University (2009TS069), the National Natural Science Foundation of China (30670874, 30570748, 30871038, and 30971215), and the National Basic Research Program of China (973 Program, Grant no.: 2009CB521904).

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Authors and Affiliations

  1. Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Public Health, Jinan, People’s Republic of China

    Mengxiong Tang, Fenghua Zhou, Wei Zhang, Zhongxiu Guo, Yuanyuan Shang, Huixia Lu, Ruijuan Lu, Yun Zhang, Yuguo Chen & Ming Zhong

  2. Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, People’s Republic of China

    Mengxiong Tang, Ruijuan Lu & Yuguo Chen

  3. Department of Cardiology, Qilu Hospital of Shandong University, Jinan, People’s Republic of China

    Fenghua Zhou, Wei Zhang, Zhongxiu Guo, Yuanyuan Shang, Huixia Lu, Yun Zhang & Ming Zhong

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  1. Mengxiong Tang
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Correspondence to Yuguo Chen or Ming Zhong.

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Tang, M., Zhou, F., Zhang, W. et al. The role of thrombospondin-1-mediated TGF-β1 on collagen type III synthesis induced by high glucose. Mol Cell Biochem 346, 49–56 (2011). https://doi.org/10.1007/s11010-010-0590-7

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