Open Access

p27kip1 haploinsufficiency preserves myocardial function in the early stages of myocardial infarction via Atg5‑mediated autophagy flux restoration

  • Authors:
    • Ningtian Zhou
    • Qiong Huang
    • Weili Cheng
    • Yingbin Ge
    • Dianfu Li
    • Junhong Wang
  • View Affiliations

  • Published online on: September 2, 2019     https://doi.org/10.3892/mmr.2019.10632
  • Pages: 3840-3848
  • Copyright: © Zhou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Myocardial infarction (MI) is a leading cause of mortality in adults worldwide. Over the last two decades, gene therapy has been a hot topic in cardiology, and there has been a focus on cell cycle inhibitors and their protective effects on the myocardium post‑MI. In our previous study, the haploinsufficiency of p27kip1 (p27) was demonstrated to improve cardiac function in mice post‑MI by promoting angiogenesis and myocardium protection through the secretion of growth factors. Autophagy is an adaptive response of cells to environmental changes, such as nutrient deprivation, ischemia and hypoxia. The appropriate regulation of autophagy may improve myocardial function by preventing apoptosis of cardiomyocytes. In this study, we used immunoassays, transmission electron microscopy and cardiac ultrasound to confirm that p27 haploinsufficiency prevents myocardial apoptosis by restoring autophagy protein 5‑mediated autophagy flux in the early stages of MI. The present study provides a novel method for studying MI or ischemic heart disease therapy.

References

1 

Saleh M and Ambrose JA: Understanding myocardial infarction. F1000Res. 7:F10002018. View Article : Google Scholar : PubMed/NCBI

2 

Magnoni M, Berteotti M, Norata GD, Limite LR, Peretto G, Cristell N, Maseri A and Cianflone D: Applicability of the 2013 ACC/AHA risk assessment and cholesterol treatment guidelines in the real world: Results from a multiethnic case-control study. Ann med. 48:282–292. 2016. View Article : Google Scholar : PubMed/NCBI

3 

Ramanathan K, Abel JG, Park JE, Fung A, Mathew V, Taylor CM, Mancini GBJ, Gao M, Ding L, Verma S, et al: Surgical versus percutaneous coronary revascularization in patients with diabetes and acute coronary syndromes. J Am Coll Cardiol. 70:2995–3006. 2017. View Article : Google Scholar : PubMed/NCBI

4 

Scimia MC, Gumpert AM and Koch WJ: Cardiovascular gene therapy for myocardial infarction. Expert Opin Biol Ther. 14:183–195. 2014. View Article : Google Scholar : PubMed/NCBI

5 

Wang N, Tong G, Yang J, Zhou Z, Pan H, Huo Y, Xu J, Zhang X, Ling F and Li P: Effect of hepatocyte growth-promoting factors on myocardial ischemia during exercise in patients with severe coronary artery disease. Int Heart J. 50:291–299. 2009. View Article : Google Scholar : PubMed/NCBI

6 

Shen J, Xie Y, Liu Z, Zhang S, Wang Y, Jia L, Wang Y, Cai Z, Ma H and Xiang M: Increased myocardial stiffness activates cardiac microvascular endothelial cell via VEGF paracrine signaling in cardiac hypertrophy. J Mol Cell Cardiol. 122:140–151. 2018. View Article : Google Scholar : PubMed/NCBI

7 

Kaminsky SM, Rosengart TK, Rosenberg J, Chiuchiolo MJ, Van de Graaf B, Sondhi D and Crystal RG: Gene therapy to stimulate angiogenesis to treat diffuse coronary artery disease. Human Gene Ther. 24:948–963. 2013. View Article : Google Scholar

8 

Zhao Q, Huang J, Wang D, Chen L, Sun D and Zhao C: Endothelium-specific CYP2J2 overexpression improves cardiac dysfunction by promoting angiogenesis via Jagged1/Notch1 signaling. J Mol Cell Cardiol. 123:118–127. 2018. View Article : Google Scholar : PubMed/NCBI

9 

Zhou N, Fu Y, Wang Y, Chen P, Meng H, Guo S, Zhang M, Yang Z and Ge Y: p27(kip1) haplo-insufficiency improves cardiac function in early-stages of myocardial infarction by protecting myocardium and increasing angiogenesis by promoting IKK activation. Sci Rep. 4:59782014. View Article : Google Scholar : PubMed/NCBI

10 

Koff A and Polyak K: p27KIP1, an inhibitor of cyclin-dependent kinases. Prog Cell Cycle Res. 1:141–147. 1995. View Article : Google Scholar : PubMed/NCBI

11 

Li Y, Ding X, Fan P, Guo J, Tian X, Feng X, Zheng J, Tian P, Ding C and Xue W: Inactivation of p27(kip1) promoted nonspecific inflammation by enhancing macrophage proliferation in islet transplantation. Endocrinology. 157:4121–4132. 2016. View Article : Google Scholar : PubMed/NCBI

12 

Marone M, Bonanno G, Rutella S, Leone G, Scambia G and Pierelli L: Survival and cell cycle control in early hematopoiesis: Role of bcl-2, and the cyclin dependent kinase inhibitors P27 and P21. Leuk Lymphoma. 43:51–57. 2002. View Article : Google Scholar : PubMed/NCBI

13 

Rehman G, Shehzad A, Khan AL and Hamayun M: Role of AMP-activated protein kinase in cancer therapy. Arch Pharm (Weinhim). 347:457–468. 2014. View Article : Google Scholar

14 

Rossi A, Kontarakis Z, Gerri C, Nolte H, Holper S, Kruger M and Stainier DY: Genetic compensation induced by deleterious mutations but not gene knockdowns. Nature. 524:230–233. 2015. View Article : Google Scholar : PubMed/NCBI

15 

Deter RL, Baudhuin P and De Duve C: Participation of lysosomes in cellular autophagy induced in rat liver by glucagon. J Cell Biol. 35:C11–C16. 1967. View Article : Google Scholar : PubMed/NCBI

16 

Wang Y, Liu J, Tao Z, Wu P, Cheng W, Du Y, Zhou N, Ge Y and Yang Z: Exogenous HGF prevents cardiomyocytes from apoptosis after hypoxia via up-regulating cell autophagy. Cell Physiol Biochem. 38:2401–2413. 2016. View Article : Google Scholar : PubMed/NCBI

17 

Dai SN, Hou AJ, Zhao SM, Chen XM, Huang HT, Chen BH and Kong HL: Ginsenoside Rb1 ameliorates autophagy of hypoxia cardiomyocytes from neonatal rats via AMP-activated protein kinase pathway. Chin J Integr Med. 25:521–528. 2019. View Article : Google Scholar : PubMed/NCBI

18 

Ponnusamy M, Li PF and Wang K: Understanding cardiomyocyte proliferation: An insight into cell cycle activity. Cell Mol Life Sci. 74:1019–1034. 2017. View Article : Google Scholar : PubMed/NCBI

19 

Ding Y, Kim JK, Kim SI, Na HJ, Jun SY, Lee SJ and Choi ME: TGF-{beta}1 protects against mesangial cell apoptosis via induction of autophagy. J Biol Chem. 285:37909–37919. 2010. View Article : Google Scholar : PubMed/NCBI

20 

Sun X, Momen A, Wu J, Noyan H, Li R, von Harsdorf R and Husain M: p27 protein protects metabolically stressed cardiomyocytes from apoptosis by promoting autophagy. J Biol Chem. 289:16924–16935. 2014. View Article : Google Scholar : PubMed/NCBI

21 

Arya R and White K: Cell death in development: Signaling pathways and core mechanisms. Semin Cell Dev Biol. 39:12–19. 2015. View Article : Google Scholar : PubMed/NCBI

22 

Stegehuis VE, Wijntjens GW, Piek JJ and van de Hoef TP: Fractional flow reserve or coronary flow reserve for the assessment of myocardial perfusion: Implications of FFR as an imperfect reference standard for myocardial ischemia. Curr Cardiol Rep. 20:772018. View Article : Google Scholar : PubMed/NCBI

23 

Lopez B, Gonzalez A, Ravassa S, Beaumont J, Moreno MU, San Jose G, Querejeta R and Diez J: Circulating biomarkers of myocardial fibrosis: The need for a reappraisal. J Am Coll Cardiol. 65:2449–2456. 2015. View Article : Google Scholar : PubMed/NCBI

24 

Delgado V, van Bommel RJ, Bertini M, Borleffs CJ, Marsan NA, Arnold CT, Nucifora G, van de Veire NR, Ypenburg C, Boersma E, et al: Relative merits of left ventricular dyssynchrony, left ventricular lead position, and myocardial scar to predict long-term survival of ischemic heart failure patients undergoing cardiac resynchronization therapy. Circulation. 123:70–78. 2011. View Article : Google Scholar : PubMed/NCBI

25 

Sun T, Li MY, Li PF and Cao JM: MicroRNAs in cardiac autophagy: Small molecules and big role. Cells. 7:E1042018. View Article : Google Scholar : PubMed/NCBI

26 

Li H, Peng X, Wang Y, Cao S, Xiong L, Fan J, Wang Y, Zhuang S, Yu X and Mao H: Atg5-mediated autophagy deficiency in proximal tubules promotes cell cycle G2/M arrest and renal fibrosis. Autophagy. 12:1472–1486. 2016. View Article : Google Scholar : PubMed/NCBI

27 

Booth LA, Tavallai S, Hamed HA, Cruickshanks N and Dent P: The role of cell signalling in the crosstalk between autophagy and apoptosis. Cell Signal. 26:549–555. 2014. View Article : Google Scholar : PubMed/NCBI

28 

Kaminskyy VO and Zhivotovsky B: Free radicals in cross talk between autophagy and apoptosis. Antioxid Redox Signal. 21:86–102. 2014. View Article : Google Scholar : PubMed/NCBI

29 

Huang WQ, Wen JL, Lin RQ, Wei P and Huang F: Effects of mTOR/NF-κB signaling pathway and high thoracic epidural anesthesia on myocardial ischemia-reperfusion injury via autophagy in rats. J Cell Physiol. 233:6669–6678. 2018. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

October 2019
Volume 20 Issue 4

Print ISSN: 1791-2997
Online ISSN:1791-3004

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Zhou, N., Huang, Q., Cheng, W., Ge, Y., Li, D., & Wang, J. (2019). p27kip1 haploinsufficiency preserves myocardial function in the early stages of myocardial infarction via Atg5‑mediated autophagy flux restoration. Molecular Medicine Reports, 20, 3840-3848. https://doi.org/10.3892/mmr.2019.10632
MLA
Zhou, N., Huang, Q., Cheng, W., Ge, Y., Li, D., Wang, J."p27kip1 haploinsufficiency preserves myocardial function in the early stages of myocardial infarction via Atg5‑mediated autophagy flux restoration". Molecular Medicine Reports 20.4 (2019): 3840-3848.
Chicago
Zhou, N., Huang, Q., Cheng, W., Ge, Y., Li, D., Wang, J."p27kip1 haploinsufficiency preserves myocardial function in the early stages of myocardial infarction via Atg5‑mediated autophagy flux restoration". Molecular Medicine Reports 20, no. 4 (2019): 3840-3848. https://doi.org/10.3892/mmr.2019.10632