Endothelial Cell Aging and Autophagy Dysregulation

Basheer   Abdullah   Marzoog

doi:10.2174/0118715257275690231129101408

Abstract

Entropy is a natural process that affects all living cells, including senescence, an irreversible physiological process that impairs cell homeostasis. Age is a significant factor in disease development, and the pathogenesis of endothelial cell aging is multifactorial. Autophagy dysfunction accelerates endothelial cell aging and cell death, while autophagy preserves endothelial cell youthfulness through intracellular homeostasis and gene expression regulation. Sirt, mTORC1, and AMPK are youthfulness genes that induce autophagy by inhibiting mTOR and upregulating FIP200/Atg13/ULK1. Aged endothelial cells have decreased levels of Lamin B1, γH2AX, Ki67, BrdU, PCNA, and SA β-Gal. Maintaining healthy young endothelial cells can prevent most cardiovascular diseases. Autophagy targeting is a potential future therapeutic strategy to modify endothelial cell age and potentially slow or reverse the aging process. This article provides state-of-the-art research on the role of autophagy in endothelial cell aging. Hypothesizing that autophagy dysregulation is associated with early endothelial cell dysfunction and further clinical sequelae, including atherosclerosis formation, leading to various cardiovascular diseases.

Keywords: Aging, autophagy, endothelial cell, sirtuin, pathogenesis, senolytics, longevity.

« Previous Next »

Graphical Abstract

[1]
Pilard, M.; Ollivier, E.L.; Gourdou-Latyszenok, V.; Couturaud, F.; Lemarié, C.A. Endothelial cell phenotype, a major determinant of venous thrombo-inflammation. Front. Cardiovasc. Med.,  2022, 9, 864735.
 [http://dx.doi.org/10.3389/fcvm.2022.864735] [PMID:  35528838]

[2]
Yang, J.H. Loss of epigenetic information as a cause of mammalian aging. SSRN, 2021.
 [http://dx.doi.org/10.2139/ssrn.3951490]

[3]
 Cardiovascular diseases (CVDs). Available from:
          https://www.who.int/news-room/fact-sheets/detail/cardiovascul
ar-diseases-(cvds) (Accessed on: 01.06.2022).

[4]
Donato, A.J.; Machin, D.R.; Lesniewski, L.A. Mechanisms of dysfunction in the aging vasculature and role in age-related disease. Circ. Res.,  2018, 123(7), 825-848.
 [http://dx.doi.org/10.1161/CIRCRESAHA.118.312563] [PMID:  30355078]

[5]
López-Otín, C.; Blasco, M.A.; Partridge, L.; Serrano, M.; Kroemer, G. The hallmarks of aging. Cell. Elsevier B.V.,  2013, 153(6), 1194-1217.
 [PMID:  23746838]

[6]
Meng, L.; Zhang, Y.; Luo, Y.; Gong, T.; Liu, D. Chronic stress a potential suspect zero of atherosclerosis: A systematic review. Front. Cardiovasc. Med.,  2021, 8, 738654.
 [http://dx.doi.org/10.3389/fcvm.2021.738654] [PMID:  34988123]

[7]
Hernandez-Segura, A.; Nehme, J.; Demaria, M. Hallmarks of cellular senescence. Trends Cell Biol.,  2018, 28(6), 436-453.
 [http://dx.doi.org/10.1016/j.tcb.2018.02.001] [PMID:  29477613]

[8]
Campisi, J. d’Adda di, F.F. Cellular senescence: When bad things happen to good cells. Nat. Rev. Mol. Cell Biol.,  2007, 8(9), 729-740.
 [http://dx.doi.org/10.1038/nrm2233] [PMID:  17667954]

[9]
Liu, F.; Hamer, M.A.; Deelen, J.; Lall, J.S.; Jacobs, L.; van Heemst, D.; Murray, P.G.; Wollstein, A.; de Craen, A.J.M.; Uh, H.W.; Zeng, C.; Hofman, A.; Uitterlinden, A.G.; Houwing-Duistermaat, J.J.; Pardo, L.M.; Beekman, M.; Slagboom, P.E.; Nijsten, T.; Kayser, M.; Gunn, D.A. The MC1R gene and youthful looks. Curr. Biol.,  2016, 26(9), 1213-1220.
 [http://dx.doi.org/10.1016/j.cub.2016.03.008] [PMID:  27133870]

[10]
Menghini, R.; Casagrande, V.; Marino, A.; Marchetti, V.; Cardellini, M.; Stoehr, R.; Rizza, S.; Martelli, E.; Greco, S.; Mauriello, A.; Ippoliti, A.; Martelli, F.; Lauro, R.; Federici, M. MiR-216a: A link between endothelial dysfunction and autophagy. Cell Death Dis.,  2014, 5(1), e1029.
 [http://dx.doi.org/10.1038/cddis.2013.556] [PMID:  24481443]

[11]
Coppé, J.P.; Desprez, P.Y.; Krtolica, A.; Campisi, J. The senescence-associated secretory phenotype: The dark side of tumor suppression. Annu. Rev. Pathol.,  2010, 5(1), 99-118.
 [http://dx.doi.org/10.1146/annurev-pathol-121808-102144] [PMID:  20078217]

[12]
Katsuumi, G. Vascular senescence in cardiovascular and metabolic diseases. Front. Cardiovasc. Med.,  2018, 5, 18.

[13]
Sun, Y.; Wang, X.; Liu, T.; Zhu, X.; Pan, X. The multifaceted role of the SASP in atherosclerosis: From mechanisms to therapeutic opportunities. Cell Biosci.,  2022, 12(1), 74.
 [http://dx.doi.org/10.1186/s13578-022-00815-5] [PMID:  35642067]

[14]
LaRocca, T.J.; Henson, G.D.; Thorburn, A.; Sindler, A.L.; Pierce, G.L.; Seals, D.R. Translational evidence that impaired autophagy contributes to arterial ageing. J. Physiol.,  2012, 590(14), 3305-3316.
 [http://dx.doi.org/10.1113/jphysiol.2012.229690] [PMID:  22570377]

[15]
Rodier, F.; Muñoz, D.P.; Teachenor, R.; Chu, V.; Le, O.; Bhaumik, D.; Coppé, J.P.; Campeau, E.; Beauséjour, C.M.; Kim, S.H.; Davalos, A.R.; Campisi, J. DNA-SCARS: Distinct nuclear structures that sustain damage-induced senescence growth arrest and inflammatory cytokine secretion. J. Cell Sci.,  2011, 124(1), 68-81.
 [http://dx.doi.org/10.1242/jcs.071340] [PMID:  21118958]

[16]
Laberge, R.M.; Sun, Y.; Orjalo, A.V.; Patil, C.K.; Freund, A.; Zhou, L.; Curran, S.C.; Davalos, A.R.; Wilson-Edell, K.A.; Liu, S.; Limbad, C.; Demaria, M.; Li, P.; Hubbard, G.B.; Ikeno, Y.; Javors, M.; Desprez, P.Y.; Benz, C.C.; Kapahi, P.; Nelson, P.S.; Campisi, J. MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nat. Cell Biol.,  2015, 17(8), 1049-1061.
 [http://dx.doi.org/10.1038/ncb3195] [PMID:  26147250]

[17]
Freund, A.; Patil, C.K.; Campisi, J. p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype. EMBO J.,  2011, 30(8), 1536-1548.
 [http://dx.doi.org/10.1038/emboj.2011.69] [PMID:  21399611]

[18]
Nacarelli, T.; Lau, L.; Fukumoto, T.; Zundell, J.; Fatkhutdinov, N.; Wu, S.; Aird, K.M.; Iwasaki, O.; Kossenkov, A.V.; Schultz, D.; Noma, K.; Baur, J.A.; Schug, Z.; Tang, H.Y.; Speicher, D.W.; David, G.; Zhang, R. NAD+ metabolism governs the proinflammatory senescence-associated secretome. Nat. Cell Biol.,  2019, 21(3), 397-407.
 [http://dx.doi.org/10.1038/s41556-019-0287-4] [PMID:  30778219]

[19]
Chini, C.; Hogan, K.A.; Warner, G.M.; Tarragó, M.G.; Peclat, T.R.; Tchkonia, T.; Kirkland, J.L.; Chini, E. The NADase CD38 is induced by factors secreted from senescent cells providing a potential link between senescence and age-related cellular NAD+ decline. Biochem. Biophys. Res. Commun.,  2019, 513(2), 486-493.
 [http://dx.doi.org/10.1016/j.bbrc.2019.03.199] [PMID:  30975470]

[20]
Wiley, C.D.; Velarde, M.C.; Lecot, P.; Liu, S.; Sarnoski, E.A.; Freund, A.; Shirakawa, K.; Lim, H.W.; Davis, S.S.; Ramanathan, A.; Gerencser, A.A.; Verdin, E.; Campisi, J. Mitochondrial dysfunction induces senescence with a distinct secretory phenotype. Cell Metab.,  2016, 23(2), 303-314.
 [http://dx.doi.org/10.1016/j.cmet.2015.11.011] [PMID:  26686024]

[21]
Chen, D.; Bruno, J.; Easlon, E.; Lin, S.J.; Cheng, H.L.; Alt, F.W.; Guarente, L. Tissue-specific regulation of SIRT1 by calorie restriction. Genes Dev.,  2008, 22(13), 1753-1757.
 [http://dx.doi.org/10.1101/gad.1650608] [PMID:  18550784]

[22]
Nadtochiy, S.M. SIRT1-mediated acute cardioprotection. Am. J. Physiol. Heart Circ. Physiol.,  2011, 301(4), H1506-H1512.

[23]
Yamakuchi, M.; Hashiguchi, T. Endothelial cell aging: How miRNAs contribute? J. Clin. Med.,  2018, 7(7), 170.
 [http://dx.doi.org/10.3390/jcm7070170] [PMID:  29996516]

[24]
Yazdanyar, A.; Newman, A.B. The burden of cardiovascular disease in the elderly: Morbidity, mortality, and costs. Clin. Geriatr. Med.,  2009, 25(4), 563-577. [vii].
 [http://dx.doi.org/10.1016/j.cger.2009.07.007] [PMID: 19944261]

[25]
Lapierre, L.R.; Kumsta, C.; Sandri, M.; Ballabio, A.; Hansen, M. Transcriptional and epigenetic regulation of autophagy in aging. Autophagy,  2015, 11(6), 867-880.
 [http://dx.doi.org/10.1080/15548627.2015.1034410] [PMID:  25836756]

[26]
Jiang, F. Autophagy in vascular endothelial cells. Clin. Exp. Pharmacol. Physiol.,  2016, 43(11), 1021-1028.
 [http://dx.doi.org/10.1111/1440-1681.12649] [PMID:  27558982]

[27]
Mai, S.; Brehm, N.; Auburger, G.; Bereiter-Hahn, J.; Jendrach, M. Age-related dysfunction of the autophago-lysosomal pathway in human endothelial cells. Pflugers Arch.,  2019, 471(8), 1065-1078.
 [http://dx.doi.org/10.1007/s00424-019-02288-x] [PMID:  31222491]

[28]
Salemkour, Y.; Lenoir, O. Endothelial autophagy dysregulation in diabetes. Cells,  2023, 12(6), 947.
 [http://dx.doi.org/10.3390/cells12060947] [PMID:  36980288]

[29]
Sachdev, U.; Lotze, M.T. Perpetual change: Autophagy, the endothelium, and response to vascular injury. J. Leukoc. Biol.,  2017, 102(2), 221-235.
 [http://dx.doi.org/10.1189/jlb.3RU1116-484RR] [PMID:  28626046]

[30]
Lin, J.R.; Shen, W.L.; Yan, C.; Gao, P.J. Downregulation of dynamin-related protein 1 contributes to impaired autophagic flux and angiogenic function in senescent endothelial cells. Arterioscler. Thromb. Vasc. Biol.,  2015, 35(6), 1413-1422.
 [http://dx.doi.org/10.1161/ATVBAHA.115.305706] [PMID:  25908761]

[31]
Marzoog, B. Endothelial dysfunction under the scope of arterial hypertension, coronary heart disease, and diabetes mellitus using the angioscan. Cardiovasc. Hematol. Agents Med. Chem., 2023.
 [http://dx.doi.org/10.2174/0118715257246589231018053646]

[32]
Marzoog, B.A. Autophagy behavior in endothelial cell regeneration. Curr. Mol. Med., 2022.

[33]
Marzoog, B.A.; Vlasova, T.I. Beta-cell autophagy under the scope of hypoglycemic drugs; possible mechanism as a novel therapeutic target. Obes. Metab.,  2022, 18(4), 465-470.
 [http://dx.doi.org/10.14341/omet12778]

[34]
Marzoog, B.A. Systemic and local hypothermia in the context of cell regeneration. Cryo Lett.,  2022, 43(2), 66-73.
 [http://dx.doi.org/10.54680/fr22210110112] [PMID:  36626147]

[35]
Marzoog, B.A. Tree of life: Endothelial cell in norm and disease, the good guy is a partner in crime! Anat. Cell Biol.,  2023, 56(2), 166-178.
 [http://dx.doi.org/10.5115/acb.22.190] [PMID:  36879408]

[36]
Marzoog, B.A. Endothelial cell autophagy in the context of disease development. Anat. Cell Biol.,  2023, 56(1), 16-24.
 [http://dx.doi.org/10.5115/acb.22.098] [PMID:  36267005]

[37]
Abdullah, M.B. Autophagy as an anti-senescent in aging neurocytes. Curr. Mol. Med.,  2023, 23.
 [PMID:  36683318]

[38]
Marzoog, B. Lipid behavior in metabolic syndrome pathophysiology. Curr. Diabetes Rev.,  2022, 18(6), e150921196497.
 [http://dx.doi.org/10.2174/1573399817666210915101321] [PMID:  34525924]

[39]
Marzoog, B.A. Local lung fibroblast autophagy in the context of lung fibrosis pathogenesis. Curr. Respir. Med. Rev.,  2023, 19(1), 6-11.
 [http://dx.doi.org/10.2174/1573398X19666221130141600]

[40]
Marzoog, B.A. Autophagy in cancer cell transformation: A potential novel therapeutic strategy. Curr. Cancer Drug Targets,  2022, 22(9), 749-756.
 [http://dx.doi.org/10.2174/1568009622666220428102741] [PMID:  36062863]

[41]
Marzoog, B.A.; Vlasova, T.I. Myocardiocyte autophagy in the context of myocardiocytes regeneration: A potential novel therapeutic strategy. Egypt. J. Med. Hum. Genet.,  2022, 23(1), 41.

[42]
Marzoog, B.A. Recent advances in molecular biology of metabolic syndrome pathophysiology: Endothelial dysfunction as a potential therapeutic target. J. Diabetes Metab. Disord.,  2022, 21(2), 1903-1911.
 [http://dx.doi.org/10.1007/s40200-022-01088-y] [PMID:  36065330]

[43]
Abdullah, M.B. Adaptive and compensatory mechanisms of the cardiovascular system and disease risk factors in young males and females. New Emirates Med. J.,  2023, 4(1)

[44]
Marzoog, B.A. The metabolic syndrome puzzles; Possible pathogenesis and management. Curr. Diabetes Rev.,  2023, 19(4), e290422204258.
 [http://dx.doi.org/10.2174/1573399818666220429100411] [PMID:  35507784]

[45]
Marzoog, B.A.; Vlasova, T.I. Transcription factors in deriving β cell regeneration: A potential novel therapeutic target. Curr. Mol. Med.,  2022, 22(5), 421-430.
 [http://dx.doi.org/10.2174/1566524021666210712144638] [PMID:  34931980]

[46]
Marzoog, B.A. Transcription factors – the essence of heart regeneration: A potential novel therapeutic strategy. Curr. Mol. Med.,  2023, 23(3), 232-238.
 [http://dx.doi.org/10.2174/1566524022666220216123650] [PMID:  35170408]

[47]
Marzoog, B.A.; Vlasova, T.I. Membrane lipids under norm and pathology. Eur J Clin Exp Med,  2021, 19(1), 59-75.
 [http://dx.doi.org/10.15584/ejcem.2021.1.9]

[48]
Carracedo, J. Endothelial cell senescence in the pathogenesis of endothelial dysfunction. In: Endothelial Dysfunction; IntechOpen, 2018. 

[49]
Donato, A.J. Cellular and molecular biology of aging endothelial cells. J. Mol. Cell. Cardiol.,  2015, 89, 122.

[50]
Harris, J.; Hartman, M.; Roche, C.; Zeng, S.G.; O’Shea, A.; Sharp, F.A.; Lambe, E.M.; Creagh, E.M.; Golenbock, D.T.; Tschopp, J.; Kornfeld, H.; Fitzgerald, K.A.; Lavelle, E.C. Autophagy controls IL-1β secretion by targeting pro-IL-1β for degradation. J. Biol. Chem.,  2011, 286(11), 9587-9597.
 [http://dx.doi.org/10.1074/jbc.M110.202911] [PMID:  21228274]

[51]
Dembic, Z. The cytokines of the immune system: the role of cytokines in disease related to immune response; Academic Press, 2015. 

[52]
Guixé-Muntet, S.; de Mesquita, F.C.; Vila, S.; Hernández-Gea, V.; Peralta, C.; García-Pagán, J.C.; Bosch, J.; Gracia-Sancho, J. Cross-talk between autophagy and KLF2 determines endothelial cell phenotype and microvascular function in acute liver injury. J. Hepatol.,  2017, 66(1), 86-94.
 [http://dx.doi.org/10.1016/j.jhep.2016.07.051] [PMID:  27545498]

[53]
Liu, J.; Bi, X.; Chen, T.; Zhang, Q.; Wang, S-X.; Chiu, J-J.; Liu, G-S.; Zhang, Y.; Bu, P.; Jiang, F. Shear stress regulates endothelial cell autophagy via redox regulation and Sirt1 expression. Cell Death Dis.,  2015, 6(7), e1827.
 [http://dx.doi.org/10.1038/cddis.2015.193] [PMID:  26181207]

[54]
Hua, Y.; Zhang, J.; Liu, Q.; Su, J.; Zhao, Y.; Zheng, G.; Yang, Z.; Zhuo, D.; Ma, C.; Fan, G. The induction of endothelial autophagy and its role in the development of atherosclerosis. Front. Cardiovasc. Med.,  2022, 9, 831847.
 [http://dx.doi.org/10.3389/fcvm.2022.831847] [PMID:  35402552]

[55]
Sánchez-Martín, P.; Saito, T.; Komatsu, M. p62/SQSTM 1: ‘Jack of all trades’ in health and cancer. FEBS J.,  2019, 286(1), 8-23.
 [http://dx.doi.org/10.1111/febs.14712] [PMID:  30499183]

[56]
Lu, Y.; Brommer, B.; Tian, X.; Krishnan, A.; Meer, M.; Wang, C.; Vera, D.L.; Zeng, Q.; Yu, D.; Bonkowski, M.S.; Yang, J.H.; Zhou, S.; Hoffmann, E.M.; Karg, M.M.; Schultz, M.B.; Kane, A.E.; Davidsohn, N.; Korobkina, E.; Chwalek, K.; Rajman, L.A.; Church, G.M.; Hochedlinger, K.; Gladyshev, V.N.; Horvath, S.; Levine, M.E.; Gregory-Ksander, M.S.; Ksander, B.R.; He, Z.; Sinclair, D.A. Reprogramming to recover youthful epigenetic information and restore vision. Nature,  2020, 588(7836), 124-129.
 [http://dx.doi.org/10.1038/s41586-020-2975-4] [PMID:  33268865]

[57]
Donato, A.J.; Gano, L.B.; Eskurza, I.; Silver, A.E.; Gates, P.E.; Jablonski, K.; Seals, D.R. Vascular endothelial dysfunction with aging: Endothelin-1 and endothelial nitric oxide synthase. Am. J. Physiol. Heart Circ. Physiol.,  2009, 297(1), H425-H432.
 [http://dx.doi.org/10.1152/ajpheart.00689.2008] [PMID:  19465546]

[58]
Ting, K.K.; Coleman, P.; Zhao, Y.; Vadas, M.A.; Gamble, J.R. The aging endothelium. Vascular Biology,  2021, 3(1), R35-R47.
 [http://dx.doi.org/10.1530/VB-20-0013] [PMID:  33880430]

[59]
Sinclair, D.; Rinaldi, C. SIRT1 activating compounds. US Patent App. 17/284691, 2021.

[60]
González-Moro, A. NLRP3 inflammasome in vascular disease: A recurrent villain to combat pharmacologically. Antioxidants,  2022, 11(2)

[61]
Schwefel, K.; Spiegler, S.; Much, C.D.; Felbor, U.; Rath, M. CRISPR/Cas9-mediated generation of human endothelial cell knockout models of CCM disease. Methods Mol. Biol.,  2020, 2152, 169-177.
 [http://dx.doi.org/10.1007/978-1-0716-0640-7_13] [PMID:  32524552]

[62]
Abdullah, M.B. Cell physiological behavior in the context of local hypothermia. New Emirates Med. J,  2023, 5.

[63]
Marzoog, B.A. Autophagy behavior in post-myocardial infarction injury. Cardiovasc. Hematol. Disord. Drug Targets,  2023, 23(1), 2-10.
 [http://dx.doi.org/10.2174/1871529X23666230503123612] [PMID:  37138481]

[64]
Marzoog, B.A. Autophagy behavior in endothelial cell dysfunction. New Emir. Med. J,  2023, 5

[65]
Suzuki, K.; Ohkuma, M.; Someya, A.; Mita, T.; Nagaoka, I. Human cathelicidin peptide LL-37 induces cell death in autophagy-dysfunctional endothelial cells. J. Immunol.,  2022, 208(9), 2163-2172.
 [http://dx.doi.org/10.4049/jimmunol.2100050] [PMID:  35387840]

Rights & Permissions Print Cite

Article Metrics

40

1

Journal Information

For Authors

For Editors

For Reviewers

Explore Articles

Open Access

Open Access Articles

For Visitors

DOI https://dx.doi.org/10.2174/0118715257275690231129101408	Print ISSN 1871-5257
Publisher Name Bentham Science Publisher	Online ISSN 1875-6182

Cardiovascular & Hematological Agents in Medicinal Chemistry

Endothelial Cell Aging and Autophagy Dysregulation

Abstract

Graphical Abstract

Medicinal Plants with Beneficial Properties on Diabetes and Hypertension

Cardiovascular & Hematological Agents in Medicinal Chemistry

Endothelial Cell Aging and Autophagy Dysregulation

Abstract

Graphical Abstract

Call for Papers in Thematic Issues

Medicinal Plants with Beneficial Properties on Diabetes and Hypertension

Related Journals

Related Books