Skip to main content
SpringerLink
Log in

MitoNEET in Perivascular Adipose Tissue Prevents Arterial Stiffness in Aging Mice

  • ORIGINAL ARTICLE
  • Published:
Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Abstract

Purpose

Arterial stiffness is an inevitable consequence of the aging process and is considered an early stage in the development of cardiovascular diseases. The perivascular adipose tissue (PVAT) is a distinct functional integral layer of the vasculature actively involved in blood pressure regulation and atherosclerosis development via PVAT-derived paracrine/autocrine factors. However, there is little knowledge regarding the relationship between PVAT and arterial stiffness.

Methods

Using unique mice lacking PVAT, high-fat diet-induced obesity, and in mice overexpressing brown adipocyte selective mitoNEET, we investigated the relationship between PVAT and arterial stiffness in mice.

Results

We found that lack of PVAT enhanced arterial stiffness in aging mice. High-fat diet feeding of aging C57BL/6J wild-type mice significantly induced hypertrophic PVAT and enhanced arterial stiffness. Furthermore, the expression of mitoNEET, a mitochondrial membrane protein related to energy expenditure, was significantly increased by pioglitazone treatment, while reduced in the hypertrophic PVAT induced by high-fat diet. Overexpression of mitoNEET in PVAT reduced the expression of inflammatory genes and was associated with lower pulse wave velocity in aging mice.

Conclusions

These data indicate that local PVAT homeostasis especially inflammation in PVAT is associated with arterial stiffness development. Pioglitazone-induced mitoNEET in PVAT prevents PVAT inflammation and is negatively associated with arterial stiffness. These findings provide new experimental insight into the roles of pioglitazone on PVAT in arterial stiffness and indicate that PVAT might be a target to treat or prevent cardiovascular disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Wilson PW, D’Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation. 1998;97(18):1837–47.

    Article  CAS  Google Scholar 

  2. Wang TJ, Gona P, Larson MG, Tofler GH, Levy D, Newton-Cheh C, et al. Multiple biomarkers for the prediction of first major cardiovascular events and death. N Engl J Med. 2006;355(25):2631–9.

    Article  CAS  Google Scholar 

  3. Laurent S, Boutouyrie P. Recent advances in arterial stiffness and wave reflection in human hypertension. Hypertension. 2007;49(6):1202–6.

    Article  CAS  Google Scholar 

  4. O’Rourke MF, Safar ME. Relationship between aortic stiffening and microvascular disease in brain and kidney: cause and logic of therapy. Hypertension. 2005;46(1):200–4.

    Article  Google Scholar 

  5. McEniery CM, Wilkinson IB, Avolio AP. Age, hypertension and arterial function. Clin Exp Pharmacol Physiol. 2007;34(7):665–71.

    Article  CAS  Google Scholar 

  6. Wagenseil JE, Mecham RP. Elastin in large artery stiffness and hypertension. J Cardiovasc Transl Res. 2012;5(3):264–73.

    Article  Google Scholar 

  7. Kelly R, Hayward C, Avolio A, O’Rourke M. Noninvasive determination of age-related changes in the human arterial pulse. Circulation. 1989;80(6):1652–9.

    Article  CAS  Google Scholar 

  8. Yildiz O. Vascular smooth muscle and endothelial functions in aging. Ann N Y Acad Sci. 2007;1100:353–60.

    Article  CAS  Google Scholar 

  9. Osborne-Pellegrin M, Labat C, Mercier N, Challande P, Lacolley P. Changes in aortic stiffness related to elastic fiber network anomalies in the Brown Norway rat during maturation and aging. Am J Physiol Heart Circ Physiol. 2010;299(1):H144–52.

    Article  CAS  Google Scholar 

  10. Chang L, Milton H, Eitzman DT, Chen YE. Paradoxical roles of perivascular adipose tissue in atherosclerosis and hypertension. Circ J. 2012;77(1):11–8.

    Article  Google Scholar 

  11. Chang L, Villacorta L, Li R, Hamblin M, Xu W, Dou C, et al. Loss of perivascular adipose tissue on peroxisome proliferator-activated receptor-gamma deletion in smooth muscle cells impairs intravascular thermoregulation and enhances atherosclerosis. Circulation. 2012;126(9):1067–78.

    Article  CAS  Google Scholar 

  12. Lee YC, Chang HH, Chiang CL, Liu CH, Yeh JI, Chen MF, et al. Role of perivascular adipose tissue-derived methyl palmitate in vascular tone regulation and pathogenesis of hypertension. Circulation. 2011;124(10):1160–71.

    Article  Google Scholar 

  13. Seifalian AM, Filippatos TD, Joshi J, Mikhailidis DP. Obesity and arterial compliance alterations. Curr Vasc Pharmacol. 2010;8(2):155–68.

    Article  CAS  Google Scholar 

  14. Selcuk A, Bulucu F, Kalafat F, Cakar M, Demirbas S, Karaman M, et al. Skinfold thickness as a predictor of arterial stiffness: obesity and fatness linked to higher stiffness measurements in hypertensive patients. Clin Exp Hypertens. 2013;35(6):459–64.

    Article  Google Scholar 

  15. Thanassoulis G, Massaro JM, Corsini E, Rogers I, Schlett CL, Meigs JB, et al. Periaortic adipose tissue and aortic dimensions in the Framingham heart study. J Am Heart Assoc. 2012;1(6):e000885.

    Article  Google Scholar 

  16. Kusminski CM, Holland WL, Sun K, Park J, Spurgin SB, Lin Y, et al. MitoNEET-driven alterations in adipocyte mitochondrial activity reveal a crucial adaptive process that preserves insulin sensitivity in obesity. Nat Med. 2012;18(10):1539–49.

    Article  CAS  Google Scholar 

  17. Wiley SE, Murphy AN, Ross SA, van der Geer P, Dixon JE. MitoNEET is an iron-containing outer mitochondrial membrane protein that regulates oxidative capacity. Proc Natl Acad Sci U S A. 2007;104(13):5318–23.

    Article  CAS  Google Scholar 

  18. Harashima K, Hayashi J, Miwa T, Tsunoda T. Long-term pioglitazone therapy improves arterial stiffness in patients with type 2 diabetes mellitus. Metabolism. 2009;58(6):739–45.

    Article  CAS  Google Scholar 

  19. Colca JR, McDonald WG, Waldon DJ, Leone JW, Lull JM, Bannow CA, et al. Identification of a novel mitochondrial protein (“mitoNEET”) cross-linked specifically by a thiazolidinedione photoprobe. Am J Physiol Endocrinol Metab. 2004;286(2):E252–60.

    Article  CAS  Google Scholar 

  20. Xiong W, Zhao X, Garcia-Barrio MT, Zhang J, Lin J, Chen YE, et al. MitoNEET in perivascular adipose tissue blunts atherosclerosis under mild cold condition in mice. Front Physiol. 2017;8:1032.

    Article  Google Scholar 

  21. Kusminski CM, Park J, Scherer PE. MitoNEET-mediated effects on browning of white adipose tissue. Nat Commun. 2014;5:3962.

    Article  CAS  Google Scholar 

  22. Chang L, Villacorta L, Zhang J, Garcia-Barrio MT, Yang K, Hamblin M, et al. Vascular smooth muscle cell-selective peroxisome proliferator-activated receptor-gamma deletion leads to hypotension. Circulation. 2009;119(16):2161–9.

    Article  CAS  Google Scholar 

  23. Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D, et al. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J. 2006;27(21):2588–605.

    Article  Google Scholar 

  24. Gustafson B, Gogg S, Hedjazifar S, Jenndahl L, Hammarstedt A, Smith U. Inflammation and impaired adipogenesis in hypertrophic obesity in man. Am J Physiol Endocrinol Metab. 2009;297(5):E999–E1003.

    Article  CAS  Google Scholar 

  25. Pirro M, Schillaci G, Savarese G, Gemelli F, Vaudo G, Siepi D, et al. Low-grade systemic inflammation impairs arterial stiffness in newly diagnosed hypercholesterolaemia. Eur J Clin Investig. 2004;34(5):335–41.

    Article  CAS  Google Scholar 

  26. Zieman SJ, Melenovsky V, Kass DA. Mechanisms, pathophysiology, and therapy of arterial stiffness. Arterioscler Thromb Vasc Biol. 2005;25(5):932–43.

    Article  CAS  Google Scholar 

  27. Boden G, Cheung P, Mozzoli M, Fried SK. Effect of thiazolidinediones on glucose and fatty acid metabolism in patients with type 2 diabetes. Metabolism. 2003;52(6):753–9.

    Article  CAS  Google Scholar 

  28. Hallakou S, Doare L, Foufelle F, Kergoat M, Guerre-Millo M, Berthault MF, et al. Pioglitazone induces in vivo adipocyte differentiation in the obese Zucker fa/fa rat. Diabetes. 1997;46(9):1393–9.

    Article  CAS  Google Scholar 

  29. Okuno A, Tamemoto H, Tobe K, Ueki K, Mori Y, Iwamoto K, et al. Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats. J Clin Invest. 1998;101(6):1354–61.

    Article  CAS  Google Scholar 

  30. Kiyici S, Ersoy C, Kaderli A, Fazlioglu M, Budak F, Duran C, et al. Effect of rosiglitazone, metformin and medical nutrition treatment on arterial stiffness, serum MMP-9 and MCP-1 levels in drug naive type 2 diabetic patients. Diabetes Res Clin Pract. 2009;86(1):44–50.

    Article  CAS  Google Scholar 

  31. Yu J, Jin N, Wang G, Zhang F, Mao J, Wang X. Peroxisome proliferator-activated receptor gamma agonist improves arterial stiffness in patients with type 2 diabetes mellitus and coronary artery disease. Metabolism. 2007;56(10):1396–401.

    Article  CAS  Google Scholar 

  32. Ryan KE, McCance DR, Powell L, McMahon R, Trimble ER. Fenofibrate and pioglitazone improve endothelial function and reduce arterial stiffness in obese glucose tolerant men. Atherosclerosis. 2007;194(2):e123–30.

    Article  CAS  Google Scholar 

  33. Nedergaard J, Bengtsson T, Cannon B. Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab. 2007;293(2):E444–52.

    Article  CAS  Google Scholar 

  34. Nedergaard J, Bengtsson T, Cannon B. Three years with adult human brown adipose tissue. Ann N Y Acad Sci. 2010;1212:E20–36.

    Article  Google Scholar 

  35. Kim S, Moustaid-Moussa N. Secretory, endocrine and autocrine/paracrine function of the adipocyte. J Nutr. 2000;130(12):3110S–5S.

    Article  CAS  Google Scholar 

  36. Smith RE, Horwitz BA. Brown fat and thermogenesis. Physiol Rev. 1969;49(2):330–425.

    Article  CAS  Google Scholar 

  37. De Schutter A, Lavie CJ, Patel DA, Artham SM, Milani RV. Relation of body fat categories by Gallagher classification and by continuous variables to mortality in patients with coronary heart disease. Am J Cardiol. 2013;111(5):657–60.

    Article  Google Scholar 

  38. Clark AL, Chyu J, Horwich TB. The obesity paradox in men versus women with systolic heart failure. Am J Cardiol. 2012;110(1):77–82.

    Article  Google Scholar 

  39. Wu J, Bostrom P, Sparks LM, Ye L, Choi JH, Giang AH, et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell. 2012;150(2):366–76.

    Article  CAS  Google Scholar 

  40. Calabro P, Yeh ET. Obesity, inflammation, and vascular disease: the role of the adipose tissue as an endocrine organ. Subcell Biochem. 2007;42:63–91.

    Article  Google Scholar 

  41. Verhagen SN, Vink A, van der Graaf Y, Visseren FL. Coronary perivascular adipose tissue characteristics are related to atherosclerotic plaque size and composition. A post-mortem study. Atherosclerosis. 2012;225(1):99–104.

    Article  CAS  Google Scholar 

  42. Shields KJ, Stolz D, Watkins SC, Ahearn JM. Complement proteins C3 and C4 bind to collagen and elastin in the vascular wall: a potential role in vascular stiffness and atherosclerosis. Clin Transl Sci. 2011;4(3):146–52.

    Article  CAS  Google Scholar 

  43. Chen JY, Tsai PJ, Tai HC, Tsai RL, Chang YT, Wang MC, et al. Increased aortic stiffness and attenuated lysyl oxidase activity in obesity. Arterioscler Thromb Vasc Biol. 2013;33(4):839–46.

    Article  Google Scholar 

  44. Chang L, Xiong W, Zhao X, Fan Y, Guo Y, Garcia-Barrio M, et al. Bmal1 in perivascular adipose tissue regulates resting phase blood pressure through transcriptional regulation of angiotensinogen. Circulation. 2018;138:67–79.

    Article  CAS  Google Scholar 

  45. Hamblin M, Chang L, Zhang H, Yang K, Zhang J, Chen YE. Vascular smooth muscle cell peroxisome proliferator-activated receptor-gamma mediates pioglitazone-reduced vascular lesion formation. Arterioscler Thromb Vasc Biol. 2011;31(2):352–9.

    Article  CAS  Google Scholar 

  46. Hamblin M, Chang L, Zhang H, Yang K, Zhang J, Chen YE. Vascular smooth muscle cell peroxisome proliferator-activated receptor-gamma deletion promotes abdominal aortic aneurysms. J Vasc Surg. 2010;52(4):984–93.

    Article  Google Scholar 

  47. Vernay A, Marchetti A, Sabra A, Jauslin TN, Rosselin M, Scherer PE, et al. MitoNEET-dependent formation of intermitochondrial junctions. Proc Natl Acad Sci U S A. 2017;114(31):8277–82.

    Article  CAS  Google Scholar 

Download references

Funding

This work was supported by NIH grants HL122664 (to L. Chang) and HL088391 (to Y.E. Chen).

Author information

Authors and Affiliations

  1. Cardiovascular Center, Department of Internal Medicine, Michigan University of Michigan, 026-214N NCRC, 2800 Plymouth Rd., Ann Arbor, MI, 48109, USA

    Lin Chang, Xiangjie Zhao, Minerva Garcia-Barrio, Jifeng Zhang & Y. Eugene Chen

Authors
  1. Lin Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiangjie Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Minerva Garcia-Barrio
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jifeng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Y. Eugene Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

LC designed the studies, LC and XZ performed the experiments, and JZ generated mitoNEET-Tg mice. LC and YC analyzed the data; LC and MGB wrote the paper.

Corresponding author

Correspondence to Lin Chang.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Statement

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. This article does not contain any studies with human participants and/or specimens.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chang, L., Zhao, X., Garcia-Barrio, M. et al. MitoNEET in Perivascular Adipose Tissue Prevents Arterial Stiffness in Aging Mice. Cardiovasc Drugs Ther 32, 531–539 (2018). https://doi.org/10.1007/s10557-018-6809-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10557-018-6809-7

Keywords

Search

Navigation