Protein homeostasis in the aged and diseased heart

Abstract

Protein homeostasis, the balance between protein synthesis and degradation, requires the clearance of misfolded and aggregated proteins and is therefore considered to be an essential aspect of establishing a physiologically effective proteome. Aging alters this balance, termed “proteostasis”, resulting in the progressive accumulation of misfolded and aggregated proteins. Defective proteostasis leads to the functional deterioration of diverse regulatory processes during aging and is implicated in the etiology of multiple pathological conditions underlying a variety of neurodegenerative diseases and in age-dependent cardiovascular disease. Detergent-insoluble protein aggregates have been reported by us in both aged and hypertensive hearts. The protein constituents were found to overlap with protein aggregates seen in neurodegenerative diseases such as Alzheimer’s disease. Therefore, targeting these protein components of aggregates may be a promising therapeutic strategy for cardiovascular pathologies associated with aging, ischemia, and/or hypertension.

Keywords

Protein aggregation / cardiovascular disease / aging / myocardial ischemia / hypertension

References

[1] Monte F, Agnetti G. Protein post-translational modifications and misfolding: new concepts in heart failure.Proteomics Clin Appl2014;8:534-42 PMCID:PMC4560347

[2] Anfinsen CB.Principles that govern the folding of protein chains.Science1973;181:223-30

[3] Hartl FU.Molecular chaperones in cellular protein folding.Nature1996;381:571-9

[4] Stefani M.Protein aggregation and aggregate toxicity: new insights into protein folding, misfolding diseases and biological evolution.J Mol Med2003;81:678-99

[5] Cao SS.Unfolded protein response.Curr Biol2012;22:R622-6

[6] Lebeaupin C,Hazari Y,Chevet E.Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease.J Hepatol2018;69:927-47

[7] Stolz A,Dikic I.Cargo recognition and trafficking in selective autophagy.Nat Cell Biol2014;16:495-501

[8] Wang M.Protein misfolding in the endoplasmic reticulum as a conduit to human disease.Nature2016;529:326-35

[9] Vembar SS.One step at a time: endoplasmic reticulum-associated degradation.Nat Rev Mol Cell Biol2008;9:944-57 PMCID:PMC2654601

[10] Needham PG.How early studies on secreted and membrane protein quality control gave rise to the ER associated degradation (ERAD) pathway: the early history of ERAD.Biochim Biophys Acta2013;1833:2447-57 PMCID:PMC3723753

[11] Bonifacino JS,Klausner RD.Colocalized transmembrane determinants for ER degradation and subunit assembly explain the intracellular fate of TCR chains.Cell1990;63:503-13

[12] Ren J,Sowers JR,Zhang Y.Endoplasmic reticulum stress and unfolded protein response in cardiovascular diseases.Nat Rev Cardiol2021;18:499-521

[13] Johnston JA,Kopito RR.Aggresomes: a cellular response to misfolded proteins.J Cell Biol1998;143:1883-98 PMCID:PMC2175217

[14] García-Mata R,Sorscher EJ.Characterization and dynamics of aggresome formation by a cytosolic GFP-chimera.J Cell Biol1999;146:1239-54 PMCID:PMC2156127

[15] Ding WX.Sorting, recognition and activation of the misfolded protein degradation pathways through macroautophagy and the proteasome.Autophagy2008;4:141-50

[16] Reiss Y,Ravid T.Releasing the lockdown: an emerging role for the ubiquitin-proteasome system in the breakdown of transient protein inclusions.Biomolecules2020;10:1168 PMCID:PMC7463783

[17] Day SM.The ubiquitin proteasome system in human cardiomyopathies and heart failure.Am J Physiol Heart Circ Physiol2013;304:H1283-93 PMCID:PMC4073948

[18] Li Y,Wu H.Ubiquitination-proteasome system (UPS) and autophagy two main protein degradation machineries in response to cell stress.Cells2022;11:851 PMCID:PMC8909305

[19] George AJ,Charles AJ,Mabb AM.A comprehensive atlas of E3 ubiquitin ligase mutations in neurological disorders.Front Genet2018;9:29 PMCID:PMC5817383

[20] Sun L.The novel functions of ubiquitination in signaling.Curr Opin Cell Biol2004;16:119-26

[21] Brinkmann K,Hoppe T.Regulation of the DNA damage response by ubiquitin conjugation.Front Genet2015;6:98 PMCID:PMC4354423

[22] Diefenbacher M.Stabilization of nuclear oncoproteins by RNF4 and the ubiquitin system in cancer.Mol Cell Oncol2017;4:e1260671 PMCID:PMC5287002

[23] Glickman MH.The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction.Physiol Rev2002;82:373-428

[24] Grice GL.The recognition of ubiquitinated proteins by the proteasome.Cell Mol Life Sci2016;73:3497-506 PMCID:PMC4980412

[25] Willis MS,Pulinilkunnil T,Tannu M.The role of ubiquitin ligases in cardiac disease.J Mol Cell Cardiol2014;71:43-53 PMCID:PMC4011977

[26] Wang C.The interplay between autophagy and the ubiquitin-proteasome system in cardiac proteotoxicity.Biochim Biophys Acta2015;1852:188-94 PMCID:PMC4277934

[27] Griffin TA,Cruz M.Immunoproteasome assembly: cooperative incorporation of interferon gamma (IFN-gamma)-inducible subunits.J Exp Med1998;187:97-104 PMCID:PMC2199179

[28] Li J,Wang X.Enhancement of proteasome function by PA28α overexpression protects against oxidative stress.FASEB J2011;25:883-93 PMCID:PMC3042837

[29] Li J,Su H,Robbins J.Enhancement of proteasomal function protects against cardiac proteinopathy and ischemia/reperfusion injury in mice.J Clin Invest2011;121:3689-700 PMCID:PMC3163952

[30] Lecker SH,Mitch WE.Protein degradation by the ubiquitin-proteasome pathway in normal and disease states.J Am Soc Nephrol2006;17:1807-19

[31] Petroski MD.The ubiquitin system, disease, and drug discovery.BMC Biochem2008;9:S7 PMCID:PMC2582801

[32] Fang S,Ludwig RL,Weissman AM.Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53.J Biol Chem2000;275:8945-51

[33] Toth A,Qin LL.Differential regulation of cardiomyocyte survival and hypertrophy by MDM2, an E3 ubiquitin ligase.J Biol Chem2006;281:3679-89

[34] Birks EJ,Enesa K.Elevated p53 expression is associated with dysregulation of the ubiquitin-proteasome system in dilated cardiomyopathy.Cardiovasc Res2008;79:472-80

[35] Scruggs SB,Wang D,Ping P.Post-translational modification of cardiac proteasomes: functional delineation enabled by proteomics.Am J Physiol Heart Circ Physiol2012;303:H9-18 PMCID:PMC3404648

[36] Oliva J.Proteasome and organs ischemia-reperfusion injury.Int J Mol Sci2017;19:106 PMCID:PMC5796056

[37] Predmore JM,Davis F.Ubiquitin proteasome dysfunction in human hypertrophic and dilated cardiomyopathies.Circulation2010;121:997-1004 PMCID:PMC2857348

[38] Wang X.Proteasomal and lysosomal protein degradation and heart disease.J Mol Cell Cardiol2014;71:16-24 PMCID:PMC4011941

[39] Liu J,Huang W.Impairment of the ubiquitin-proteasome system in desminopathy mouse hearts.FASEB J2006;20:362-4

[40] Depre C,Yan L.Activation of the cardiac proteasome during pressure overload promotes ventricular hypertrophy.Circulation2006;114:1821-8

[41] Chen Q,Horak KM.Intrasarcoplasmic amyloidosis impairs proteolytic function of proteasomes in cardiomyocytes by compromising substrate uptake.Circ Res2005;97:1018-26

[42] Lu K,Jentsch S.Receptor oligomerization guides pathway choice between proteasomal and autophagic degradation.Nat Cell Biol2017;19:732-9

[43] Hu C,Xu H.Inadequate ubiquitination-proteasome coupling contributes to myocardial ischemia-reperfusion injury.J Clin Invest2018;128:5294-306 PMCID:PMC6264645

[44] Glick D,Macleod KF.Autophagy: cellular and molecular mechanisms.J Pathol2010;221:3-12 PMCID:PMC2990190

[45] Gao G,Yan M.Rapamycin regulates the balance between cardiomyocyte apoptosis and autophagy in chronic heart failure by inhibiting mTOR signaling.Int J Mol Med2020;45:195-209 PMCID:PMC6889932

[46] Anversa P,Beltrami CA,Kajstura J.Myocyte death and growth in the failing heart.Lab Invest1998;78:767-86

[47] Narula J,Virmani R.Apoptosis in myocytes in end-stage heart failure.N Engl J Med1996;335:1182-9

[48] Majno G.Apoptosis, oncosis, and necrosis. An overview of cell death.Am J Pathol1995;146:3-15. PMCID:PMC1870771

[49] Ikeda S,Sadoshima J.The role of autophagy in death of cardiomyocytes.J Mol Cell Cardiol2022;165:1-8 PMCID:PMC8940676

[50] Collier JJ,Oláhová M,Taylor RW.Emerging roles of ATG7 in human health and disease.EMBO Mol Med2021;13:e14824 PMCID:PMC8649875

[51] Nakai A,Takeda T.The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress.Nat Med2007;13:619-24

[52] Ma X,Foyil SR.Impaired autophagosome clearance contributes to cardiomyocyte death in ischemia/reperfusion injury.Circulation2012;125:3170-81 PMCID:PMC3397471

[53] Evans S,Wang X.Targeting the autophagy-lysosome pathway in a pathophysiologically relevant murine model of reversible heart failure.JACC Basic Transl Sci2022;7:1214-28 PMCID:PMC9831862

[54] Wu P,Li F.Myocardial upregulation of cathepsin d by ischemic heart disease promotes autophagic flux and protects against cardiac remodeling and heart failure.Circ Heart Fail2017;10 PMCID:PMC5535800

[55] Shimomura H,Hayashi T,Isomura T.Autophagic degeneration as a possible mechanism of myocardial cell death in dilated cardiomyopathy.Jpn Circ J2001;65:965-8

[56] Nishino I,Tanji K.Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease).Nature2000;406:906-10

[57] Nah J,Sadoshima J.The role of autophagic cell death in cardiac disease.J Mol Cell Cardiol2022;173:16-24

[58] Morales CR,Lavandero S.Oxidative stress and autophagy in cardiovascular homeostasis.Antioxid Redox Signal2014;20:507-18 PMCID:PMC3894700

[59] Luo C,Wang H.Mitochondrial accumulation under oxidative stress is due to defects in autophagy.J Cell Biochem2013;114:212-9

[60] Terman A,Eaton JW,Brunk UT.Aging of cardiac myocytes in culture: oxidative stress, lipofuscin accumulation, and mitochondrial turnover.Ann N Y Acad Sci2004;1019:70-7

[61] Wang Y,Wang X.atg7-Based autophagy activation reverses doxorubicin-induced cardiotoxicity.Circ Res2021;129:e166-82 PMCID:PMC8484060

[62] B'chir W,Carraro V.The eIF2α/ATF4 pathway is essential for stress-induced autophagy gene expression.Nucleic Acids Res2013;41:7683-99 PMCID:PMC3763548

[63] Wang J,Huang H.Hepatitis C virus core protein activates autophagy through EIF2AK3 and ATF6 UPR pathway-mediated MAP1LC3B and ATG12 expression.Autophagy2014;10:766-84 PMCID:PMC5119055

[64] Deegan S,Gorman AM.Stress-induced self-cannibalism: on the regulation of autophagy by endoplasmic reticulum stress.Cell Mol Life Sci2013;70:2425-41

[65] Gade P,Maachani UB.An IFN-γ-stimulated ATF6-C/EBP-β-signaling pathway critical for the expression of death associated protein kinase 1 and induction of autophagy.Proc Natl Acad Sci USA2012;109:10316-21 PMCID:PMC3387052

[66] Zalckvar E,Eisenstein M.Phosphorylation of beclin 1 by DAP-kinase promotes autophagy by weakening its interactions with Bcl-2 and Bcl-XL.Autophagy2009;5:720-2

[67] Korolchuk VI,Menzies FM.Autophagy inhibition compromises degradation of ubiquitin-proteasome pathway substrates.Mol Cell2009;33:517-27 PMCID:PMC2669153

[68] Tian Z,Hu C,Liu J.AUTOPHAGIC-lysosomal inhibition compromises ubiquitin-proteasome system performance in a p62 dependent manner in cardiomyocytes.PLoS One2014;9:e100715 PMCID:PMC4069113

[69] Zheng Q,Wang X.Interplay between the ubiquitin-proteasome system and autophagy in proteinopathies.Int J Physiol Pathophysiol Pharmacol2009;1:127-42 PMCID:PMC2856956

[70] Cha-Molstad H,Hwang J.Amino-terminal arginylation targets endoplasmic reticulum chaperone BiP for autophagy through p62 binding.Nat Cell Biol2015;17:917-29 PMCID:PMC4490096

[71] Ciechanover A.Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies.Exp Mol Med2015;47:e147 PMCID:PMC4351408

[72] Blessing NA,Chadee DN.The E3 ligase CHIP mediates ubiquitination and degradation of mixed-lineage kinase 3.Mol Cell Biol2014;34:3132-43 PMCID:PMC4135596

[73] Zhang HT,He QY,Zha ZG.The E3 ubiquitin ligase CHIP mediates ubiquitination and proteasomal degradation of PRMT5.Biochim Biophys Acta2016;1863:335-46 PMCID:PMC5397900

[74] Cristofani R,Rusmini P.Inhibition of retrograde transport modulates misfolded protein accumulation and clearance in motoneuron diseases.Autophagy2017;13:1280-303 PMCID:PMC5584856

[75] Pan B,Parajuli N.The Calcineurin-TFEB-p62 pathway mediates the activation of cardiac macroautophagy by proteasomal malfunction.Circ Res2020;127:502-18 PMCID:PMC7416491

[76] Lee J,Zhang J.Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling.Biochem J2012;441:523-40 PMCID:PMC3258656

[77] Martins-Marques T,Pereira P,Girao H.Autophagy and ubiquitination in cardiovascular diseases.DNA Cell Biol2015;34:243-51 PMCID:PMC4389907

[78] Shirakabe A,Sciarretta S,Sadoshima J.Aging and autophagy in the heart.Circ Res2016;118:1563-76 PMCID:PMC4869999

[79] Sciarretta S,Zablocki D.The role of autophagy in the heart.Annu Rev Physiol2018;80:1-26

[80] Lee SH,Griffiths JR.HIF-1-independent mechanisms regulating metabolic adaptation in hypoxic cancer cells.Cells2021;10:2371 PMCID:PMC8472468

[81] Zimna A.Hypoxia-inducible factor-1 in physiological and pathophysiological angiogenesis: applications and therapies.Biomed Res Int2015;2015:549412 PMCID:PMC4471260

[82] Kierans SJ.Regulation of glycolysis by the hypoxia-inducible factor (HIF): implications for cellular physiology.J Physiol2021;599:23-37

[83] Koumenis C,Koritzinsky M.Regulation of protein synthesis by hypoxia via activation of the endoplasmic reticulum kinase PERK and phosphorylation of the translation initiation factor eIF2alpha.Mol Cell Biol2002;22:7405-16 PMCID:PMC135664

[84] Arsham AM,Simon MC.A novel hypoxia-inducible factor-independent hypoxic response regulating mammalian target of rapamycin and its targets.J Biol Chem2003;278:29655-60

[85] Brugarolas J,Hurley RL.Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex.Genes Dev2004;18:2893-904 PMCID:PMC534650

[86] Liu L,Jones RG,Thompson CB.Hypoxia-induced energy stress regulates mRNA translation and cell growth.Mol Cell2006;21:521-31 PMCID:PMC3153113

[87] Fels DR.The PERK/eIF2alpha/ATF4 module of the UPR in hypoxia resistance and tumor growth.Cancer Biol Ther2006;5:723-8

[88] Díaz-Bulnes P,López-Larrea C.Crosstalk between hypoxia and ER stress response: a key regulator of macrophage polarization.Front Immunol2019;10:2951 PMCID:PMC6961549

[89] Jia W,Li J.Upregulated ATF6 contributes to chronic intermittent hypoxia-afforded protection against myocardial ischemia/reperfusion injury.Int J Mol Med2016;37:1199-208 PMCID:PMC4829135

[90] Cao X,Li X,Liu X.The IRE1α-XBP1 pathway function in hypoxia-induced pulmonary vascular remodeling, is upregulated by quercetin, inhibits apoptosis and partially reverses the effect of quercetin in PASMCs.Am J Transl Res2019;11:641-54. PMCID:PMC6413268

[91] Blais JD,Bi M.Activating transcription factor 4 is translationally regulated by hypoxic stress.Mol Cell Biol2004;24:7469-82 PMCID:PMC506979

[92] Olson N.Interactions between nitric oxide and hypoxia-inducible factor signaling pathways in inflammatory disease.Nitric Oxide2011;25:125-37 PMCID:PMC3090692

[93] Woollard KJ.Monocytes in atherosclerosis: subsets and functions.Nat Rev Cardiol2010;7:77-86 PMCID:PMC2813241

[94] Peng YJ,Ramakrishnan D.Heterozygous HIF-1alpha deficiency impairs carotid body-mediated systemic responses and reactive oxygen species generation in mice exposed to intermittent hypoxia.J Physiol2006;577:705-16 PMCID:PMC1890436

[95] Nanduri J,Yuan G,Prabhakar NR.Hypoxia-inducible factors and hypertension: lessons from sleep apnea syndrome.J Mol Med2015;93:473-80 PMCID:PMC4409567

[96] Calbet JA.Chronic hypoxia increases blood pressure and noradrenaline spillover in healthy humans.J Physiol2003;551:379-86 PMCID:PMC2343162

[97] Przyklenk K,Undyala VV.Autophagy as a therapeutic target for ischaemia/reperfusion injury?.Cardiovasc Res2012;94:197-205

[98] Liu X,Xu Y,Li H.MicroRNA-223 protects neonatal rat cardiomyocytes and H9c2 cells from hypoxia-induced apoptosis and excessive autophagy via the Akt/mTOR pathway by targeting PARP-1.J Mol Cell Cardiol2018;118:133-46

[99] An J,Guo Y,Bao Q.Angiotensin receptor-neprilysin inhibitor attenuates ischemia-hypoxia-induced myocardial injury via inhibition of autophagy.Am J Transl Res2022;14:8611-20. PMCID:PMC9827305

[100] Pizzino G,Cucinotta M.Oxidative stress: harms and benefits for human health.Oxid Med Cell Longev2017;2017:8416763 PMCID:PMC5551541

[101] Rajendran P,Rengarajan T.Antioxidants and human diseases.Clin Chim Acta2014;436:332-47

[102] Ishii T,Usami H.Oxidative modification of proteasome: identification of an oxidation-sensitive subunit in 26 S proteasome.Biochemistry2005;44:13893-901

[103] Tanase M,Zolla V.Role of carbonyl modifications on aging-associated protein aggregation.Sci Rep2016;6:19311 PMCID:PMC4726109

[104] Cannizzo ES,Morozova K.Age-related oxidative stress compromises endosomal proteostasis.Cell Rep2012;2:136-49 PMCID:PMC3408590

[105] Scharf B,Yodmuang S.Age-related carbonylation of fibrocartilage structural proteins drives tissue degenerative modification.Chem Biol2013;20:922-34 PMCID:PMC3758909

[106] Münzel T,Maack C,Fuster V.Impact of oxidative stress on the heart and vasculature: part 2 of a 3-part series.J Am Coll Cardiol2017;70:212-29 PMCID:PMC5663297

[107] Breitkreuz M.A change of heart: oxidative stress in governing muscle function?.Biophys Rev2015;7:321-41 PMCID:PMC5418422

[108] Lee A,Mitsuyama S.The role of SUMO-1 in cardiac oxidative stress and hypertrophy.Antioxid Redox Signal2014;21:1986-2001 PMCID:PMC4208582

[109] Serrander L,Bedard K.NOX4 activity is determined by mRNA levels and reveals a unique pattern of ROS generation.Biochem J2007;406:105-14 PMCID:PMC1948990

[110] Bedard K.The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology.Physiol Rev2007;87:245-313

[111] Ago T,Pain J,Li H.Upregulation of Nox4 by hypertrophic stimuli promotes apoptosis and mitochondrial dysfunction in cardiac myocytes.Circ Res2010;106:1253-64 PMCID:PMC2855780

[112] Ago T,Zhai P.A redox-dependent pathway for regulating class II HDACs and cardiac hypertrophy.Cell2008;133:978-93

[113] Ikeda Y,Nagarajan N.New insights into the role of mitochondrial dynamics and autophagy during oxidative stress and aging in the heart.Oxid Med Cell Longev2014;2014:210934 PMCID:PMC4124219

[114] Li D,Wang S.Role of acetylation in doxorubicin-induced cardiotoxicity.Redox Biol2021;46:102089 PMCID:PMC8350499

[115] Wallace KB.Adriamycin-induced interference with cardiac mitochondrial calcium homeostasis.Cardiovasc Toxicol2007;7:101-7

[116] Prathumsap N,Chattipakorn SC.Effects of doxorubicin on the heart: from molecular mechanisms to intervention strategies.Eur J Pharmacol2020;866:172818

[117] Chen X,Feng M,Qian L.A novel peptide HSP-17 ameliorates oxidative stress injury and apoptosis in H9c2 cardiomyocytes by activating the PI3K/Akt pathway.Ann Transl Med2022;10:1357 PMCID:PMC9843411

[118] Li J,Brundel BJJM.Imbalance of ER and mitochondria interactions: prelude to cardiac ageing and disease?.Cells2019;8:1617 PMCID:PMC6952992

[119] Ren D,Fedorova J,He Z.Sestrin2 modulates cardiac inflammatory response through maintaining redox homeostasis during ischemia and reperfusion.Redox Biol2020;34:101556 PMCID:PMC7248240

[120] Kishimoto Y,Momiyama Y.The protective role of sestrin2 in atherosclerotic and cardiac diseases.Int J Mol Sci2021;22:1200 PMCID:PMC7865804

[121] Zhang J,Li S,Zhao P.ER stress induces myocardial dysfunction and cardiac autophagy in Sestrin2 knockout mice.Am J Transl Res2022;14:5800-11 PMCID:PMC9452346

[122] Okada K,Tsukamoto Y.Prolonged endoplasmic reticulum stress in hypertrophic and failing heart after aortic constriction: possible contribution of endoplasmic reticulum stress to cardiac myocyte apoptosis.Circulation2004;110:705-12

[123] Liu MQ,Chen LX.Endoplasmic reticulum stress: a novel mechanism and therapeutic target for cardiovascular diseases.Acta Pharmacol Sin2016;37:425-43 PMCID:PMC4820795

[124] Giordano E,Nicod N.Hydroxytyrosol attenuates tunicamycin-induced endoplasmic reticulum stress in human hepatocarcinoma cells.Mol Nutr Food Res2014;58:954-62

[125] Keylani K,Khalaji A.Endoplasmic reticulum as a target in cardiovascular diseases: is there a role for flavonoids?.Front Pharmacol2022;13:1027633 PMCID:PMC9871646

[126] Yoneda T,Urano F,Harding HP.Compartment-specific perturbation of protein handling activates genes encoding mitochondrial chaperones.J Cell Sci2004;117:4055-66

[127] Moyzis AG,Gustafsson ÅB.Mending a broken heart: the role of mitophagy in cardioprotection.Am J Physiol Heart Circ Physiol2015;308:H183-92 PMCID:PMC4312945

[128] Marí M,Colell A,Fernández-Checa JC.Mitochondrial glutathione, a key survival antioxidant.Antioxid Redox Signal2009;11:2685-700 PMCID:PMC2821140

[129] Strutynska N,Mys L.Glutathione restores the mitochondrial redox status and improves the function of the cardiovascular system in old rats.Front Physiol2022;13:1093388 PMCID:PMC9868586

[130] Chen Y,Jowdy C.Mitofusin 2-containing mitochondrial-reticular microdomains direct rapid cardiomyocyte bioenergetic responses via interorganelle Ca²⁺ crosstalk.Circ Res2012;111:863-75 PMCID:PMC3444672

[131] Gordaliza-Alaguero I,Zorzano A.Metabolic implications of organelle-mitochondria communication.EMBO Rep2019;20:e47928 PMCID:PMC6726909

[132] Collins HE,Zou L.Stromal interaction molecule 1 is essential for normal cardiac homeostasis through modulation of ER and mitochondrial function.Am J Physiol Heart Circ Physiol2014;306:H1231-9 PMCID:PMC3989749

[133] Tallquist MD.Cardiac fibroblast diversity.Annu Rev Physiol2020;82:63-78

[134] Tomasek JJ,Owens GK.Regulation of alpha-smooth muscle actin expression in granulation tissue myofibroblasts is dependent on the intronic CArG element and the transforming growth factor-beta1 control element.Am J Pathol2005;166:1343-51 PMCID:PMC1606390

[135] Daseke MJ 2nd,Chalise U,Lindsey ML.Cardiac fibroblast activation during myocardial infarction wound healing: Fibroblast polarization after MI.Matrix Biol2020;91-92:109-16 PMCID:PMC7434699

[136] van Krimpen C,Cleutjens JP.DNA synthesis in the non-infarcted cardiac interstitium after left coronary artery ligation in the rat: effects of captopril.J Mol Cell Cardiol1991;23:1245-53

[137] Volders PG,Cleutjens JP,Havenith MG.Interstitial collagen is increased in the non-infarcted human myocardium after myocardial infarction.J Mol Cell Cardiol1993;25:1317-23

[138] Azevedo PS,Minicucci MF,Zornoff LA.Cardiac remodeling: concepts, clinical impact, pathophysiological mechanisms and pharmacologic treatment.Arq Bras Cardiol2016;106:62-9 PMCID:PMC4728597

[139] Cohn JN,Olivari MT.Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure.N Engl J Med1984;311:819-23

[140] Hartupee J.Neurohormonal activation in heart failure with reduced ejection fraction.Nat Rev Cardiol2017;14:30-8 PMCID:PMC5286912

[141] Yang P,Wang L.Effects of sacubitril/valsartan on cardiac reverse remodeling and cardiac resynchronization in patients with acute myocardial infarction.Front Cardiovasc Med2022;9:1059420 PMCID:PMC9880431

[142] Zhang MX,Song Y,Li YL.Astragalus propinquus schischkin and Salvia miltiorrhiza bunge promote angiogenesis to treat myocardial ischemia via Ang-1/Tie-2/FAK pathway.Front Pharmacol2022;13:1103557 PMCID:PMC9868545

[143] Ayyadevara S,Wang X.Age- and Hypertension-associated protein aggregates in mouse heart have similar proteomic profiles.Hypertension2016;67:1006-13 PMCID:PMC4833546

[144] Erqou S,Di Angelantonio E.Apolipoprotein(a) isoforms and the risk of vascular disease: systematic review of 40 studies involving 58,000 participants.J Am Coll Cardiol2010;55:2160-7

[145] Hofman A,Breteler MM.Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer's disease in the Rotterdam Study.Lancet1997;349:151-4

[146] Zhang Y,Yan L,Bian ZY.HSP75 protects against cardiac hypertrophy and fibrosis.J Cell Biochem2011;112:1787-94

[147] Meyer GR, De Keulenaer GW, Martinet W. Role of autophagy in heart failure associated with aging.Heart Fail Rev2010;15:423-30

[148] Ingham RJ,Pawson T.The Nedd4 family of E3 ubiquitin ligases: functional diversity within a common modular architecture.Oncogene2004;23:1972-84

[149] Yamano K,Esaki M,Jensen RE.Tom20 and Tom22 share the common signal recognition pathway in mitochondrial protein import.J Biol Chem2008;283:3799-807

[150] Alagpulinsa DA,Yaccoby S.A cyclin-dependent kinase inhibitor, dinaciclib, impairs homologous recombination and sensitizes multiple myeloma cells to PARP inhibition.Mol Cancer Ther2016;15:241-50 PMCID:PMC4747838

[151] Konstantinidis K,Kitsis RN.Mechanisms of cell death in heart disease.Arterioscler Thromb Vasc Biol2012;32:1552-62 PMCID:PMC3835661

[152] Thorp EB.The myocardial unfolded protein response during ischemic cardiovascular disease.Biochem Res Int2012;2012:583170 PMCID:PMC3321442

[153] Iwai T,Inoue R,Kamo N.Mitochondrial damage during ischemia determines post-ischemic contractile dysfunction in perfused rat heart.J Mol Cell Cardiol2002;34:725-38

[154] Jin JK,Azizi K.ATF6 decreases myocardial ischemia/reperfusion damage and links ER stress and oxidative stress signaling pathways in the heart.Circ Res2017;120:862-75 PMCID:PMC5336510

[155] Ganne A,Mainali N,Shmookler Reis RJ.Physiological consequences of targeting 14-3-3 and its interacting partners in neurodegenerative diseases.Int J Mol Sci2022;23:15457 PMCID:PMC9779020

[156] Ayyadevara S,Parcon PA.Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls.Aging Cell2016;15:924-39 PMCID:PMC5013017

[157] Bowroju SK,Ayyadevara S.Design and synthesis of novel hybrid 8-hydroxy quinoline-indole derivatives as inhibitors of aβ self-aggregation and metal chelation-induced aβ aggregation.Molecules2020;25:3610 PMCID:PMC7463714

[158] Balasubramaniam M,Bowroju SK.Structural modeling of GSK3β implicates the inactive (DFG-out) conformation as the target bound by TDZD analogs.Sci Rep2020;10:18326 PMCID:PMC7591898

[159] Kakraba S,Penthala NR.A novel microtubule-binding drug attenuates and reverses protein aggregation in animal models of alzheimer’s disease.Front Mol Neurosci2019;12:310 PMCID:PMC6920216

[160] Ganne A,Griffin WST,Ayyadevara S.Glial fibrillary acidic protein: a biomarker and drug target for alzheimer’s disease.Pharmaceutics2022;14:1354 PMCID:PMC9322874

[161] Abohassan M,Alshahrani MY.In silco and in vitro approaches identify novel dual PI3K/AKT pathway inhibitors to control acute myeloid leukemia cell proliferations.Med Oncol2022;39:249

[162] Shati AA,Zaki MSA,Al-Qahtani SM.Lycopene scavenges cellular ROS, modulates autophagy and improves survival through 7SK snRNA interaction in smooth muscle cells.Cells2022;11:3617 PMCID:PMC9688495

[163] Burgoyne JR.Oxidative stress impairs autophagy through oxidation of ATG3 and ATG7.Autophagy2018;14:1092-3 PMCID:PMC6103406

[164] Bhuiyan MS,Osinska H.Enhanced autophagy ameliorates cardiac proteinopathy.J Clin Invest2013;123:5284-97 PMCID:PMC3859422

[165] Zhang P,Zhang Y,Pang S.Functional variants of the ATG7 gene promoter in acute myocardial infarction.Mol Genet Genomic Med2018;6:1209-19 PMCID:PMC6305654

[166] Balasubramaniam M,Ganne A.Aggregate interactome based on protein cross-linking interfaces predicts drug targets to limit aggregation in neurodegenerative diseases.iScience2019;20:248-64 PMCID:PMC6817627

[167] Ayyadevara S,Kakraba S,Mehta JL.Aspirin-mediated acetylation protects against multiple neurodegenerative pathologies by impeding protein aggregation.Antioxid Redox Signal2017;27:1383-96 PMCID:PMC5661865

[168] Ayyadevara S,Suri P.Proteins that accumulate with age in human skeletal-muscle aggregates contribute to declines in muscle mass and function in Caenorhabditis elegans.Aging2016;8:3486-97 PMCID:PMC5270681

[169] Bowroju SK,Lakkaniga NR.Novel hydroxybenzylamine-deoxyvasicinone hybrids as anticholinesterase therapeutics for Alzheimer's disease.Bioorg Med Chem2021;45:116311 PMCID:PMC8405574