Investigating the Mechanistic Target of Rapamycin and Analogous Pathways in Cardiovascular Diseases to Augment Cardiac Functionality
DOI:
https://doi.org/10.35516/jjps.v18i2.2313Keywords:
Coronary artery disease, ischaemic heart disease , mTOR pathwayAbstract
Cardiovascular diseases (CVDs) are the leading cause of global mortality, especially in low- to middle-income countries, with heart failure accounting for 34% of deaths, totaling 62.5 million premature deaths in the past decade. Despite initial improvements in survival rates, mortality due to heart failure remains concerning, indicating a decline in the heart’s compensatory capacity as age advances. To understand the molecular complexities of CVDs, this narrative review extensively explored databases such as Scopus, Web of Science, and PubMed using specific inclusion criteria to select articles from experimental studies, clinical trials, animal studies, and observational studies published after the year 2000. Conversely, exclusion criteria were applied to omit articles irrelevant to the topic or published before 2000. The extensive literature search revealed, surprisingly, the largely unexplored potential of targeting the mTOR pathway for the treatment of CVDs. Previous studies suggest that mTOR modulation could reshape cardiac disease pathways, though clinical evidence remains limited. Recent findings underscore mTOR dysregulation in cardiac diseases and show promise in mitigating dysfunction through mTOR inhibition, despite challenges in clinical translation. Understanding mTOR’s crosstalk with other pathways illuminates the complexity of cardiac disease. This review emphasizes mTOR’s significance in coronary artery disease (CAD) and ischemic heart disease (IHD), suggesting avenues for further research and clinical applications to improve cardiovascular disease management and reduce heart failure-related mortality.
References
Hansson G.K. Inflammation, atherosclerosis, and coronary artery disease. N. Engl. J. Med. 2005; 352(16):1685-1695. DOI: https://doi.org/10.1056/NEJMra043430
Pawitan J. Molecular pathogenesis of atherosclerosis and implication for therapy. Int. Med. J. Malays. 2010; 9(2):7-14. DOI: https://doi.org/10.31436/imjm.v9i2.712
Walpola P.L., Gotlieb A.I., Cybulsky M.I. and Langille B.L. Expression of ICAM-1 and VCAM-1 and monocyte adherence in arteries exposed to altered shear stress. Arterioscler. Thromb. Vasc. Biol. 1995; 15(1):2-10. DOI: https://doi.org/10.1161/01.ATV.15.1.2
Samson S., Mundkur L. and Kakkar V.V. Immune response to lipoproteins in atherosclerosis. Cholesterol 2012; 2012:571846. DOI: https://doi.org/10.1155/2012/571846
Düvel K., Yecies J.L., Menon S., Raman P., Lipovsky A.I., Souza A.L. et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol. Cell 2010; 39(2):171-183. DOI: https://doi.org/10.1016/j.molcel.2010.06.022
Peterson T.R., Sengupta S.S., Harris T.E., Carmack A.E., Kang S.A., Balderas E. et al. mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 2011; 146(3):408-420. DOI: https://doi.org/10.1016/j.cell.2011.06.034
Brown M.S. and Goldstein J.L. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 1997; 89(3):331-340. DOI: https://doi.org/10.1016/S0092-8674(00)80213-5
Pérez-Belmonte L.M., Moreno-Santos I., Cabrera-Bueno F., Sánchez-Espín G., Castellano D., Such M. et al. Expression of sterol regulatory element-binding proteins in epicardial adipose tissue in patients with coronary artery disease and diabetes mellitus: preliminary study. Int. J. Med. Sci. 2017; 14(3):268-274. DOI: https://doi.org/10.7150/ijms.17821
Robinet P., Védie B., Chironi G., Gariépy J., Simon A., Moatti N. et al. Characterization of polymorphic structure of SREBP-2 gene: role in atherosclerosis. Atherosclerosis 2003; 168(2):381-387. DOI: https://doi.org/10.1016/S0021-9150(03)00144-8
Halcox J.P., Schenke W.H., Zalos G., Mincemoyer R., Prasad A., Waclawiw M.A. et al. Prognostic value of coronary vascular endothelial dysfunction. Circulation 2002; 106(6):653-658. DOI: https://doi.org/10.1161/01.CIR.0000025404.78001.D8
Förstermann U. and Sessa W.C. Nitric oxide synthases: regulation and function. Eur. Heart J. 2012; 33(7):829-837. DOI: https://doi.org/10.1093/eurheartj/ehr304
Davies M.G. and Hagen P.O. The vascular endothelium. A new horizon. Ann. Surg. 1993; 218(5):593-609. DOI: https://doi.org/10.1097/00000658-199321850-00003
Yang Z. and Ming X.F. mTOR signalling: the molecular interface connecting metabolic stress, aging and cardiovascular diseases. Obes. Rev. 2012; 13 Suppl 2:58-68. DOI: https://doi.org/10.1111/j.1467-789X.2012.01038.x
Sessa W.C. eNOS at a glance. J. Cell Sci. 2004; 117(Pt 12):2427-2429. DOI: https://doi.org/10.1242/jcs.01165
Fulton D., Gratton J.P., McCabe T.J., Fontana J., Fujio Y., Walsh K. et al. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 1999; 399(6736):597-601. DOI: https://doi.org/10.1038/21218
Huang P.L. eNOS, metabolic syndrome and cardiovascular disease. Trends Endocrinol. Metab. 2009; 20(6):295-302. DOI: https://doi.org/10.1016/j.tem.2009.03.005
Dimmeler S., Dernbach E., Zeiher A.M. Phosphorylation of the endothelial nitric oxide synthase at ser-1177 is required for VEGF-induced endothelial cell migration. FEBS Lett. 2000; 477(3):258-262. DOI: https://doi.org/10.1016/S0014-5793(00)01657-4
Michell B.J., Chen Z.P., Tiganis T., Stapleton D., Katsis F., Power D.A. et al. Coordinated control of endothelial nitric-oxide synthase phosphorylation by protein kinase C and the cAMP-dependent protein kinase. J. Biol. Chem. 2001; 276(21):17625-17628. DOI: https://doi.org/10.1074/jbc.C100122200
Davignon J. and Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation 2004; 109(23 Suppl 1):III27-III32. DOI: https://doi.org/10.1161/01.CIR.0000131515.03336.f8
Tiefenbacher C.P., Bleeke T., Vahl C., Amann K., Vogt A., Kübler W. Endothelial dysfunction of coronary resistance arteries is improved by tetrahydrobiopterin in atherosclerosis. Circulation 2000; 102(18):2172-2179. DOI: https://doi.org/10.1161/01.CIR.102.18.2172
Alp N.J., McAteer M.A., Khoo J., Choudhury R.P., Channon K.M. Increased endothelial tetrahydrobiopterin synthesis by targeted transgenic GTP-cyclohydrolase I overexpression reduces endothelial dysfunction and atherosclerosis in ApoE-knockout mice. Arterioscler. Thromb. Vasc. Biol. 2004; 24(3):445-450. DOI: https://doi.org/10.1161/01.ATV.0000115637.48689.77
Peng H., Zhuang Y., Harbeck M.C., He D., Xie L., Chen W. Serine 1179 Phosphorylation of Endothelial Nitric Oxide Synthase Increases Superoxide Generation and Alters Cofactor Regulation. PLoS One 2015; 10(11):e0142854. DOI: https://doi.org/10.1371/journal.pone.0142854
Rajapakse A.G., Yepuri G., Carvas J.M., Stein S., Matter C.M., Scerri I. et al. Hyperactive S6K1 mediates oxidative stress and endothelial dysfunction in aging: inhibition by resveratrol. PLoS One 2011; 6(4):e19237. DOI: https://doi.org/10.1371/journal.pone.0019237
Tarantino G., Capone D. Inhibition of the mTOR pathway: a possible protective role in coronary artery disease. Ann. Med. 2013; 45(4):348-356. DOI: https://doi.org/10.3109/07853890.2013.770333
Marx S.O., Jayaraman T., Go L.O., Marks A.R. Rapamycin-FKBP inhibits cell cycle regulators of proliferation in vascular smooth muscle cells. Circ. Res. 1995; 76(3):412-417. DOI: https://doi.org/10.1161/01.RES.76.3.412
Jung C.H., Ro S.H., Cao J., Otto N.M., Kim D.H. mTOR regulation of autophagy. FEBS Lett. 2010; 584(7):1287-1295. DOI: https://doi.org/10.1016/j.febslet.2010.01.017
Naoum J.J., Woodside K.J., Zhang S., Rychahou P.G., Hunter G.C. Effects of rapamycin on the arterial inflammatory response in atherosclerotic plaques in Apo-E knockout mice. Transplant. Proc. 2005; 37(4):1880-1884. DOI: https://doi.org/10.1016/j.transproceed.2005.02.080
Mueller M.A., Beutner F., Teupser D., Ceglarek U., Thiery J. Prevention of atherosclerosis by the mTOR inhibitor everolimus in LDLR-/- mice despite severe hypercholesterolemia. Atherosclerosis 2008; 198(1):39-48. DOI: https://doi.org/10.1016/j.atherosclerosis.2007.09.019
Nallamothu B.K., Bradley E.H., Krumholz H.M. Time to treatment in primary percutaneous coronary intervention. N. Engl. J. Med. 2007; 357(16):1631-1638. DOI: https://doi.org/10.1056/NEJMra065985
Dazert E., Hall M.N. mTOR signaling in disease. Curr. Opin. Cell Biol. 2011; 23(6):744-755. DOI: https://doi.org/10.1016/j.ceb.2011.09.003
Zoncu R., Efeyan A., Sabatini D.M. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat. Rev. Mol. Cell Biol. 2011; 12(1):21-35.. DOI: https://doi.org/10.1038/nrm3025
Aoyagi T., Kusakari Y., Xiao C.Y., Inouye B.T., Takahashi M., Scherrer-Crosbie M. Cardiac mTOR protects the heart against ischemia-reperfusion injury. Am. J. Physiol. Heart Circ. Physiol. 2012; 303(1):H75-H85. DOI: https://doi.org/10.1152/ajpheart.00241.2012
Hung C.M., Garcia-Haro L., Sparks C.A., Guertin D.A. mTOR-dependent cell survival mechanisms. Cold Spring Harb. Perspect. Biol. 2012; 4(12):a008771. DOI: https://doi.org/10.1101/cshperspect.a008771
Ronnebaum S.M., Patterson C. The FoxO family in cardiac function and dysfunction. Annu. Rev. Physiol. 2010; 72:81-94. DOI: https://doi.org/10.1146/annurev-physiol-021909-135931
Guertin D.A., Stevens D.M., Thoreen C.C., Burds A.A., Kalaany N.Y., Moffat J. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev. Cell 2006; 11(6):859-871. DOI: https://doi.org/10.1016/j.devcel.2006.10.007
Pham F.H., Sugden P.H., Clerk A. Regulation of protein kinase B and 4E-BP1 by oxidative stress in cardiac myocytes. Circ. Res. 2000; 86(12):1252-1258. DOI: https://doi.org/10.1161/01.RES.86.12.1252
Pye J., Ardeshirpour F., McCain A., Bellinger D.A., Merricks E., Adams J. Proteasome inhibition ablates activation of NF-kappa B in myocardial reperfusion and reduces reperfusion injury. Am. J. Physiol. Heart Circ. Physiol. 2003; 284(3):H919-H926. DOI: https://doi.org/10.1152/ajpheart.00851.2002
Wiza C., Nascimento E.B., Ouwens D.M. Role of PRAS40 in Akt and mTOR signaling in health and disease. Am. J. Physiol. Endocrinol. Metab. 2012; 302(12):E1453-E1460. PMID: 22354785. DOI: https://doi.org/10.1152/ajpendo.00660.2011
Völkers M., Toko H., Doroudgar S., Din S., Quijada P., Joyo A.Y. Pathological hypertrophy amelioration by PRAS40-mediated inhibition of mTORC1. Proc. Natl. Acad. Sci. U. S. A. 2013; 110(31):12661-12666. DOI: https://doi.org/10.1073/pnas.1301455110
Inoki K., Li Y., Xu T., Guan K.L. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev. 2003; 17(15):1829-1834. DOI: https://doi.org/10.1101/gad.1110003
Sciarretta S., Zhai P., Volpe M., Sadoshima J. Pharmacological modulation of autophagy during cardiac stress. J. Cardiovasc. Pharmacol. 2012; 60(3):235-241. DOI: https://doi.org/10.1097/FJC.0b013e3182575f61
Zhai P., Sciarretta S., Galeotti J., Volpe M., Sadoshima J. Differential roles of GSK-3β during myocardial ischemia and ischemia/reperfusion. Circ. Res. 2011; 109(5):502-511. DOI: https://doi.org/10.1161/CIRCRESAHA.111.249532
Matsui Y., Takagi H., Qu X., Abdellatif M., Sakoda H., Asano T. Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circ. Res. 2007; 100(6):914-922. DOI: https://doi.org/10.1161/01.RES.0000261924.76669.36
Juhaszova M., Zorov D.B., Kim S.H., Pepe S., Fu Q., Fishbein K.W. Glycogen synthase kinase-3beta mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore. J. Clin. Invest. 2004; 113(11):1535-1549. DOI: https://doi.org/10.1172/JCI200419906
Fuglesteg B.N., Tiron C., Jonassen A.K., Mjøs O.D., Ytrehus K. Pretreatment with insulin before ischaemia reduces infarct size in Langendorff-perfused rat hearts. Acta Physiol. (Oxf.) 2009; 195(2):273-282. DOI: https://doi.org/10.1111/j.1748-1716.2008.01901.x
Sciarretta S., Forte M., Frati G., Sadoshima J. New insights into the role of mTOR signaling in the cardiovascular system. Circ. Res. 2018; 122(3):489-505. DOI: https://doi.org/10.1161/CIRCRESAHA.117.311147
Sanches-Silva A., Testai L., Nabavi S.F., Battino M., Pandima Devi K., Tejada S., et al. Therapeutic potential of polyphenols in cardiovascular diseases: Regulation of mTOR signaling pathway. Pharmacol. Res. 2020; 152:104626. https://doi.org/10.1016/j.phrs.2019.104626 DOI: https://doi.org/10.1016/j.phrs.2019.104626
Bishu K., Ogut O., Kushwaha S., Mohammed S.F., Ohtani T., Xu X., et al. Anti-remodeling effects of rapamycin in experimental heart failure: dose response and interaction with angiotensin receptor blockade. PLoS One. 2013; 8:e81325. DOI: https://doi.org/10.1371/journal.pone.0081325
Griffin S.J., Leaver J.K., Irving G.J. Impact of metformin on cardiovascular disease: a meta-analysis of randomised trials among people with type 2 diabetes. Diabetologia. 2017; 60:1620-1629. DOI: https://doi.org/10.1007/s00125-017-4337-9
K P., V M. A review of safety, quality, regulation, and delivery approaches for phytopharmaceuticals. Jordan J. Pharm. Sci. 2024 Jun. Available from: https://jjournals.ju.edu.jo/index.php/jjps/article/view/1768
Kzar H.H., Al-Gazally M.E., Wtwt M.A. Everolimus loaded NPs with FOL targeting: preparation, characterization and study of its cytotoxicity action on MCF-7 breast cancer cell lines. Jordan J. Pharm. Sci. 2022 Mar 1. Available from: https://jjournals.ju.edu.jo/index.php/jjps/article/view/286 DOI: https://doi.org/10.35516/jjps.v15i1.286
Widyananda M.H., Kurniasari C.A., Alam F.M., Rizky W.C., Dings T.G.A., Ansori A.N.M., Antonius Y. Exploration of potentially bioactive compounds from fingerroot (Boesenbergia rotunda L.) as inhibitor of atherosclerosis-related proteins (CETP, ACAT1, OSC, sPLA2): An in silico study. Jordan J. Pharm. Sci. 2023 Sep 23. Available from: https://jjournals.ju.edu.jo/index.php/jjps/article/view/1609 DOI: https://doi.org/10.35516/jjps.v16i3.1609







