Compared to bortezomib treatment, multiple myeloma (MM) treatment with the proteasome inhibitor carfilzomib is associated with a higher incidence of cardiovascular adverse events. However, the mechanism underlying such cardiopathogenic side effects in MM patients remains elusive. Here, we show that carfilzomib-specific proteasome inhibition profoundly impairs cardiomyocyte contractility. Using an unbiased multiomics approach in vitro and in vivo, followed by in vitro validation, we elucidated carfilzomib-related changes in contractility proteins and cellular translation, retinol oxidative metabolism, and the angiotensin II derivative, angiotensin A. Subsequently, all-trans retinoic acid and angiotensin II type 1 receptor inhibitor prevented cardiomyocytes from experiencing carfilzomib-induced toxicity in human and murine in vitro and in vivo models through stabilization of protein and metabolic homeostasis. Our data reveal a mechanism underlying carfilzomib-induced cardiotoxicity that closely mirrors clinical observations and may open new avenues for management of such potentially lethal side effects in patients with MM.

CEITEC Masaryk University 62500 Brno Czech Republic

Department for Biomedical Research Department of Cardiology Bern University Hospital 3008 Bern Switzerland

Department of Biochemistry Faculty of Science Masaryk University 62500 Brno Czech Republic

Department of Biology Faculty of Medicine Masaryk University 62500 Brno Czech Republic

Department of Internal Medicine 2 University Hospital of Würzburg 97080 Würzburg Germany

Gorlaeus Building Leiden Institute of Chemistry 2333 Leiden the Netherlands

ICRC St Anne's University Hospital 65691 Brno Czech Republic

Institute of Immunobiology HOCH Health Ostschweiz Cantonal Hospital St Gallen 9007 St Gallen Switzerland

Laboratory of Experimental Oncology Division Oncology and Hematology HOCH Health Ostschweiz Cantonal Hospital St Gallen 9007 St Gallen Switzerland

Mildred Scheel Early Career Center University Hospital of Würzburg 97080 Würzburg Germany

See more in PubMed

Kumar S.K., Rajkumar V., Kyle R.A., van Duin M., Sonneveld P., Mateos M.V., Gay F., Anderson K.C. Multiple myeloma. Nat. Rev. Dis. Primers. 2017;3 doi: 10.1038/nrdp.2017.46. PubMed DOI

Ciechanover A. The ubiquitin-proteasome pathway: on protein death and cell life. EMBO J. 1998;17:7151–7160. doi: 10.1093/emboj/17.24.7151. PubMed DOI PMC

Moreau P., San Miguel J., Sonneveld P., Mateos M.V., Zamagni E., Avet-Loiseau H., Hajek R., Dimopoulos M.A., Ludwig H., Einsele H., et al. Multiple myeloma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2017;28:iv52–iv61. doi: 10.1093/annonc/mdx096. PubMed DOI

Besse A., Besse L., Kraus M., Mendez-Lopez M., Bader J., Xin B.T., de Bruin G., Maurits E., Overkleeft H.S., Driessen C. Proteasome inhibition in multiple myeloma: head-to-head comparison of currently available proteasome inhibitors. Cell Chem. Biol. 2019;26:340–351.e3. doi: 10.1016/j.chembiol.2018.11.007. PubMed DOI

Kumar S.K., Jacobus S.J., Cohen A.D., Weiss M., Callander N., Singh A.K., Parker T.L., Menter A., Yang X., Parsons B., et al. Carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma without intention for immediate autologous stem-cell transplantation (ENDURANCE): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 2020;21:1317–1330. doi: 10.1016/S1470-2045(20)30452-6. PubMed DOI PMC

Zhou X., Besse A., Peter J., Steinhardt M.J., Vogt C., Nerreter S., Teufel E., Stanojkovska E., Xiao X., Hornburger H., et al. High-dose carfilzomib achieves superior anti-tumor activity over lowdose and recaptures response in relapsed/refractory multiple myeloma resistant to low-dose carfilzomib by co-inhibiting the beta2 and beta1 subunits of the proteasome complex. Haematologica. 2023;108:1628–1639. doi: 10.3324/haematol.2022.282225. PubMed DOI PMC

Saavedra-Garcia P., Roman-Trufero M., Al-Sadah H.A., Blighe K., Lopez-Jimenez E., Christoforou M., Penfold L., Capece D., Xiong X., Miao Y., et al. Systems level profiling of chemotherapy-induced stress resolution in cancer cells reveals druggable trade-offs. Proc. 2021;118 doi: 10.1073/pnas.2018229118. PubMed DOI PMC

Dimopoulos M.A., Moreau P., Palumbo A., Joshua D., Pour L., Hájek R., Facon T., Ludwig H., Oriol A., Goldschmidt H., et al. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Lancet Oncol. 2016;17:27–38. doi: 10.1016/S1470-2045(15)00464-7. PubMed DOI

Cornell R.F., Ky B., Weiss B.M., Dahm C.N., Gupta D.K., Du L., Carver J.R., Cohen A.D., Engelhardt B.G., Garfall A.L., et al. Prospective study of cardiac events during proteasome inhibitor therapy for relapsed multiple myeloma. J. Clin. Oncol. 2019;37:1946–1955. doi: 10.1200/JCO.19.00231. PubMed DOI PMC

Russell S.D., Lyon A., Lenihan D.J., Moreau P., Joshua D., Chng W.-J., Palumbo A., Goldschmidt H., Hájek R., Facon T., et al. Serial echocardiographic assessment of patients (Pts) with relapsed multiple myeloma (RMM) receiving carfilzomib and dexamethasone (Kd) Vs bortezomib and dexamethasone (Vd): a substudy of the phase 3 endeavor trial (NCT01568866) Blood. 2015;126:4250.

Dimopoulos M.A., Roussou M., Gavriatopoulou M., Psimenou E., Ziogas D., Eleutherakis-Papaiakovou E., Fotiou D., Migkou M., Kanellias N., Panagiotidis I., et al. Cardiac and renal complications of carfilzomib in patients with multiple myeloma. Blood Adv. 2017;1:449–454. doi: 10.1182/bloodadvances.2016003269. PubMed DOI PMC

Efentakis P., Kremastiotis G., Varela A., Nikolaou P.E., Papanagnou E.D., Davos C.H., Tsoumani M., Agrogiannis G., Konstantinidou A., Kastritis E., et al. Molecular mechanisms of carfilzomib-induced cardiotoxicity in mice and the emerging cardioprotective role of metformin. Blood. 2019;133:710–723. doi: 10.1182/blood-2018-06-858415. PubMed DOI

Efentakis P., Psarakou G., Varela A., Papanagnou E.D., Chatzistefanou M., Nikolaou P.E., Davos C.H., Gavriatopoulou M., Trougakos I.P., Dimopoulos M.A., et al. Elucidating carfilzomib's induced cardiotoxicity in an in vivo model of aging: prophylactic potential of metformin. Int. J. Mol. Sci. 2021;22 doi: 10.3390/ijms222010956. PubMed DOI PMC

George M.Y., Dabour M.S., Rashad E., Zordoky B.N. Empagliflozin alleviates carfilzomib-induced cardiotoxicity in mice by modulating oxidative stress, inflammatory response, endoplasmic reticulum stress, and autophagy. Antioxidants. 2024;13 doi: 10.3390/antiox13060671. PubMed DOI PMC

Forghani P., Rashid A., Sun F., Liu R., Li D., Lee M.R., Hwang H., Maxwell J.T., Mandawat A., Wu R., et al. Carfilzomib treatment causes molecular and functional alterations of human induced pluripotent stem cell-derived cardiomyocytes. J. Am. Heart Assoc. 2021;10 doi: 10.1161/JAHA.121.022247. PubMed DOI PMC

Currie J., Manda V., Robinson S.K., Lai C., Agnihotri V., Hidalgo V., Ludwig R.W., Zhang K., Pavelka J., Wang Z.V., et al. Simultaneous proteome localization and turnover analysis reveals spatiotemporal features of protein homeostasis disruptions. Nat. Commun. 2024;15:2207. doi: 10.1038/s41467-024-46600-5. PubMed DOI PMC

Cole D.C., Frishman W.H. Cardiovascular complications of proteasome inhibitors used in multiple myeloma. Cardiol. Rev. 2018;26:122–129. doi: 10.1097/crd.0000000000000183. PubMed DOI

Demo S.D., Kirk C.J., Aujay M.A., Buchholz T.J., Dajee M., Ho M.N., Jiang J., Laidig G.J., Lewis E.R., Parlati F., et al. Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res. 2007;67:6383–6391. doi: 10.1158/0008-5472.CAN-06-4086. PubMed DOI

Drews O., Taegtmeyer H. Targeting the ubiquitin-proteasome system in heart disease: the basis for new therapeutic strategies. Antioxid. Redox Signal. 2014;21:2322–2343. doi: 10.1089/ars.2013.5823. PubMed DOI PMC

Ranek M.J., Zheng H., Huang W., Kumarapeli A.R., Li J., Liu J., Wang X. Genetically induced moderate inhibition of 20S proteasomes in cardiomyocytes facilitates heart failure in mice during systolic overload. J. Mol. Cell. Cardiol. 2015;85:273–281. doi: 10.1016/j.yjmcc.2015.06.014. PubMed DOI PMC

Hein S., Arnon E., Kostin S., Schönburg M., Elsässer A., Polyakova V., Bauer E.P., Klövekorn W.P., Schaper J. Progression from compensated hypertrophy to failure in the pressure-overloaded human heart. Circulation. 2003;107:984–991. doi: 10.1161/01.cir.0000051865.66123.b7. PubMed DOI

Tannous P., Zhu H., Nemchenko A., Berry J.M., Johnstone J.L., Shelton J.M., Miller F.J., Rothermel B.A., Hill J.A. Intracellular protein aggregation is a proximal trigger of cardiomyocyte autophagy. Circulation. 2008;117:3070–3078. PubMed PMC

Berenson J.R., Cartmell A., Bessudo A., Lyons R.M., Harb W., Tzachanis D., Agajanian R., Boccia R., Coleman M., Moss R.A., et al. CHAMPION-1: a phase 1/2 study of once-weekly carfilzomib and dexamethasone for relapsed or refractory multiple myeloma. Blood. 2016;127:3360–3368. doi: 10.1182/blood-2015-11-683854. PubMed DOI PMC

van der Linden W.A., Willems L.I., Shabaneh T.B., Li N., Ruben M., Florea B.I., van der Marel G.A., Kaiser M., Kisselev A.F., Overkleeft H.S. Discovery of a potent and highly beta1 specific proteasome inhibitor from a focused library of urea-containing peptide vinyl sulfones and peptide epoxyketones. Org. Biomol. Chem. 2012;10:181–194. doi: 10.1039/c1ob06554h. PubMed DOI PMC

Geurink P.P., van der Linden W.A., Mirabella A.C., Gallastegui N., de Bruin G., Blom A.E.M., Voges M.J., Mock E.D., Florea B.I., van der Marel G.A., et al. Incorporation of non-natural amino acids improves cell permeability and potency of specific inhibitors of proteasome trypsin-like sites. J. Med. Chem. 2013;56:1262–1275. doi: 10.1021/jm3016987. PubMed DOI PMC

Britton M., Lucas M.M., Downey S.L., Screen M., Pletnev A.A., Verdoes M., Tokhunts R.A., Amir O., Goddard A.L., Pelphrey P.M., et al. Selective inhibitor of proteasome's caspase-like sites sensitizes cells to specific inhibition of chymotrypsin-like sites. Chem. Biol. 2009;16:1278–1289. doi: 10.1016/j.chembiol.2009.11.015. PubMed DOI PMC

Shabaneh T.B., Downey S.L., Goddard A.L., Screen M., Lucas M.M., Eastman A., Kisselev A.F. Molecular basis of differential sensitivity of myeloma cells to clinically relevant bolus treatment with bortezomib. PLoS One. 2013;8 doi: 10.1371/journal.pone.0056132. PubMed DOI PMC

Bessen J.L., Afeyan L.K., Dančík V., Koblan L.W., Thompson D.B., Leichner C., Clemons P.A., Liu D.R. High-resolution specificity profiling and off-target prediction for site-specific DNA recombinases. Nat. Commun. 2019;10:1937. doi: 10.1038/s41467-019-09987-0. PubMed DOI PMC

Dantuma N.P., Lindsten K., Glas R., Jellne M., Masucci M.G. Short-lived green fluorescent proteins for quantifying ubiquitin/proteasome-dependent proteolysis in living cells. Nat. Biotechnol. 2000;18:538–543. doi: 10.1038/75406. PubMed DOI

Ehler E., Moore-Morris T., Lange S. Isolation and culture of neonatal mouse cardiomyocytes. J. Vis. Exp. 2013;79 doi: 10.3791/50154. PubMed DOI PMC

Huebsch N., Loskill P., Mandegar M.A., Marks N.C., Sheehan A.S., Ma Z., Mathur A., Nguyen T.N., Yoo J.C., Judge L.M., et al. Automated video-based analysis of contractility and calcium flux in human-induced pluripotent stem cell-derived cardiomyocytes cultured over different spatial scales. Tissue Eng. Part C, Methods. 2015;21:467–479. doi: 10.1089/ten.TEC.2014.0283. PubMed DOI PMC

Beauchamp P., Jackson C.B., Ozhathil L.C., Agarkova I., Galindo C.L., Sawyer D.B., Suter T.M., Zuppinger C. 3D co-culture of hiPSC-derived cardiomyocytes with cardiac fibroblasts improves tissue-like features of cardiac spheroids. Front. Mol. Biosci. 2020;7:14. doi: 10.3389/fmolb.2020.00014. PubMed DOI PMC

Pesl M., Pribyl J., Acimovic I., Vilotic A., Jelinkova S., Salykin A., Lacampagne A., Dvorak P., Meli A.C., Skladal P., Rotrekl V. Atomic force microscopy combined with human pluripotent stem cell derived cardiomyocytes for biomechanical sensing. Biosens. Bioelectron. 2016;85:751–757. doi: 10.1016/j.bios.2016.05.073. PubMed DOI

Liu C., Vyas A., Kassab M.A., Singh A.K., Yu X. The role of poly ADP-ribosylation in the first wave of DNA damage response. Nucleic Acids Res. 2017;45:8129–8141. doi: 10.1093/nar/gkx565. PubMed DOI PMC

Makia N.L., Bojang P., Falkner K.C., Conklin D.J., Prough R.A. Murine hepatic aldehyde dehydrogenase 1a1 is a major contributor to oxidation of aldehydes formed by lipid peroxidation. Chem. Biol. Interact. 2011;191:278–287. doi: 10.1016/j.cbi.2011.01.013. PubMed DOI PMC

Yang Y., Reid M.A., Hanse E.A., Li H., Li Y., Ruiz B.I., Fan Q., Kong M. SAPS3 subunit of protein phosphatase 6 is an AMPK inhibitor and controls metabolic homeostasis upon dietary challenge in male mice. Nat. Commun. 2023;14:1368. doi: 10.1038/s41467-023-36809-1. PubMed DOI PMC

Orfali N., O'Donovan T.R., Nyhan M.J., Britschgi A., Tschan M.P., Cahill M.R., Mongan N.P., Gudas L.J., McKenna S.L. Induction of autophagy is a key component of all-trans-retinoic acid-induced differentiation in leukemia cells and a potential target for pharmacologic modulation. Exp. Hematol. 2015;43:781–793.e2. doi: 10.1016/j.exphem.2015.04.012. PubMed DOI PMC

Radhakrishnan S.K., Lee C.S., Young P., Beskow A., Chan J.Y., Deshaies R.J. Transcription factor Nrf1 mediates the proteasome recovery pathway after proteasome inhibition in mammalian cells. Mol. Cell. 2010;38:17–28. doi: 10.1016/j.molcel.2010.02.029. PubMed DOI PMC

Luo M., Anderson M.E. Mechanisms of altered Ca(2)(+) handling in heart failure. Circ. Res. 2013;113:690–708. doi: 10.1161/CIRCRESAHA.113.301651. PubMed DOI PMC

Coyle K.M., Maxwell S., Thomas M.L., Marcato P. Profiling of the transcriptional response to all-trans retinoic acid in breast cancer cells reveals RARE-independent mechanisms of gene expression. Sci. Rep. 2017;7 doi: 10.1038/s41598-017-16687-6. PubMed DOI PMC

Gachon F., Olela F.F., Schaad O., Descombes P., Schibler U. The circadian PAR-domain basic leucine zipper transcription factors DBP, TEF, and HLF modulate basal and inducible xenobiotic detoxification. Cell Metab. 2006;4:25–36. doi: 10.1016/j.cmet.2006.04.015. PubMed DOI

Lai C.W., Aronson D.E., Snapp E.L. BiP availability distinguishes states of homeostasis and stress in the endoplasmic reticulum of living cells. Mol. Biol. Cell. 2010;21:1909–1921. doi: 10.1091/mbc.e09-12-1066. PubMed DOI PMC

Jankowski V., Vanholder R., Van Der Giet M., Tölle M., Karadogan S., Gobom J., Furkert J., Oksche A., Krause E., Tran T.N.A., et al. Mass-spectrometric identification of a novel angiotensin peptide in human plasma. Arterioscler. Thromb. Vasc. Biol. 2007;27:297–302. doi: 10.1161/01.atv.0000253889.09765.5f. PubMed DOI

Yang R., Smolders I., Vanderheyden P., Demaegdt H., Van Eeckhaut A., Vauquelin G., Lukaszuk A., Tourwé D., Chai S.Y., Albiston A.L., et al. Pressor and renal hemodynamic effects of the novel angiotensin a peptide are angiotensin II type 1A receptor dependent. Hypertension. 2011;57:956–964. doi: 10.1161/hypertensionaha.110.161836. PubMed DOI

Da Dalt L., Cabodevilla A.G., Goldberg I.J., Norata G.D. Cardiac lipid metabolism, mitochondrial function, and heart failure. Cardiovasc. Res. 2023;119:1905–1914. doi: 10.1093/cvr/cvad100. PubMed DOI PMC

Bazoukis G., Saplaouras A., Efthymiou P., Yiannikourides A., Liu T., Letsas K.P., Efremidis M., Lampropoulos K., Xydonas S., Tse G., Armoundas A.A. Cardiac contractility modulation in patients with heart failure - a review of the literature. Heart Fail. Rev. 2024;29:689–705. doi: 10.1007/s10741-024-10390-1. PubMed DOI

Grandin E.W., Ky B., Cornell R.F., Carver J., Lenihan D.J. Patterns of cardiac toxicity associated with irreversible proteasome inhibition in the treatment of multiple myeloma. J. Card. Fail. 2015;21:138–144. doi: 10.1016/j.cardfail.2014.11.008. PubMed DOI

Gupta A., Akki A., Wang Y., Leppo M.K., Chacko V.P., Foster D.B., Caceres V., Shi S., Kirk J.A., Su J., et al. Creatine kinase–mediated improvement of function in failing mouse hearts provides causal evidence the failing heart is energy starved. J. Clin. Investig. 2012;122:291–302. doi: 10.1172/jci57426. PubMed DOI PMC

Neubauer S. The failing heart — an engine out of fuel. N. Engl. J. Med. 2007;356:1140–1151. doi: 10.1056/nejmra063052. PubMed DOI

Yang N., Parker L.E., Yu J., Jones J.W., Liu T., Papanicolaou K.N., Talbot C.C., Jr., Margulies K.B., O'Rourke B., Kane M.A., Foster D.B. Cardiac retinoic acid levels decline in heart failure. JCI Insight. 2021;6 doi: 10.1172/jci.insight.137593. PubMed DOI PMC

Zhu Z., Zhu J., Zhao X., Yang K., Lu L., Zhang F., Shen W., Zhang R. All-trans retinoic acid ameliorates myocardial ischemia/reperfusion injury by reducing cardiomyocyte apoptosis. PLoS One. 2015;10 doi: 10.1371/journal.pone.0133414. PubMed DOI PMC

Goldsmith J., Marsh T., Asthana S., Leidal A.M., Suresh D., Olshen A., Debnath J. Ribosome profiling reveals a functional role for autophagy in mRNA translational control. Commun. Biol. 2020;3:388. doi: 10.1038/s42003-020-1090-2. PubMed DOI PMC

Van Kats J.P., Danser A.H., Van Meegen J.R., Sassen L.M., Verdouw P.D., Schalekamp M.A. Angiotensin production by the heart. Circulation. 1998;98:73–81. doi: 10.1161/01.cir.98.1.73. PubMed DOI

Sadoshima J., Izumo S. Molecular characterization of angiotensin II--induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts. Critical role of the AT1 receptor subtype. Circ. Res. 1993;73:413–423. doi: 10.1161/01.res.73.3.413. PubMed DOI

Uhal B.D., Li X., Xue A., Gao X., Abdul-Hafez A. Regulation of alveolar epithelial cell survival by the ACE-2/angiotensin 1-7/Mas axis. Am. J. Physiol. Lung Cell. Mol. Physiol. 2011;301:L269–L274. doi: 10.1152/ajplung.00222.2010. PubMed DOI PMC

Zhong J., Basu R., Guo D., Chow F.L., Byrns S., Schuster M., Loibner H., Wang X.-H., Penninger J.M., Kassiri Z., Oudit G.Y. Angiotensin-converting enzyme 2 suppresses pathological hypertrophy, myocardial fibrosis, and cardiac dysfunction. Circulation. 2010;122:717–728. doi: 10.1161/circulationaha.110.955369. PubMed DOI

Jain T., Narayanasamy H., Mikhael J., Reeder C.B., Bergsagel P.L., Mayo A., Stewart A.K., Mookadam F., Fonseca R. Systolic dysfunction associated with carfilzomib use in patients with multiple myeloma. Blood Cancer J. 2017;7:642. doi: 10.1038/s41408-017-0026-7. PubMed DOI PMC

Takeda K., Ichiki T., Funakoshi Y., Ito K., Takeshita A. Downregulation of angiotensin II type 1 receptor by all-trans retinoic acid in vascular smooth muscle cells. Hypertension. 2000;35:297–302. doi: 10.1161/01.hyp.35.1.297. PubMed DOI

Zhong J.C., Huang D.Y., Yang Y.M., Li Y.F., Liu G.F., Song X.H., Du K. Upregulation of angiotensin-converting enzyme 2 by all-trans retinoic acid in spontaneously hypertensive rats. Hypertension. 2004;44:907–912. doi: 10.1161/01.HYP.0000146400.57221.74. PubMed DOI

Wang Q., Lin Z., Wang Z., Ye L., Xian M., Xiao L., Su P., Bi E., Huang Y.-H., Qian J., et al. RARγ activation sensitizes human myeloma cells to carfilzomib treatment through OAS-RNase L innate immune pathway. Blood. 2022;139:59–72. doi: 10.1182/blood.2020009856. PubMed DOI

Shah C., Bishnoi R., Jain A., Bejjanki H., Xiong S., Wang Y., Zou F., Moreb J.S. Cardiotoxicity associated with carfilzomib: systematic review and meta-analysis. Leuk. Lymphoma. 2018;59:2557–2569. doi: 10.1080/10428194.2018.1437269. PubMed DOI

Waxman A.J., Clasen S., Hwang W.T., Garfall A., Vogl D.T., Carver J., O'Quinn R., Cohen A.D., Stadtmauer E.A., Ky B., Weiss B.M. Carfilzomib-associated cardiovascular adverse events: a systematic review and meta-analysis. JAMA Oncol. 2018;4 doi: 10.1001/jamaoncol.2017.4519. PubMed DOI PMC

de Bruin G., Xin B.T., Kraus M., van der Stelt M., van der Marel G.A., Kisselev A.F., Driessen C., Florea B.I., Overkleeft H.S. A set of activity-based probes to visualize human (immuno)proteasome activities. Angew. Chem. Int. Ed. Engl. 2016;55:4199–4203. doi: 10.1002/anie.201509092. PubMed DOI

Pesl M., Acimovic I., Pribyl J., Hezova R., Vilotic A., Fauconnier J., Vrbsky J., Kruzliak P., Skladal P., Kara T., et al. Forced aggregation and defined factors allow highly uniform-sized embryoid bodies and functional cardiomyocytes from human embryonic and induced pluripotent stem cells. Heart Vessel. 2014;29:834–846. doi: 10.1007/s00380-013-0436-9. PubMed DOI

Soriano G.P., Besse L., Li N., Kraus M., Besse A., Meeuwenoord N., Bader J., Everts B., den Dulk H., Overkleeft H.S., et al. Proteasome inhibitor-adapted myeloma cells are largely independent from proteasome activity and show complex proteomic changes, in particular in redox and energy metabolism. Leukemia. 2016;30:2198–2207. doi: 10.1038/leu.2016.102. PubMed DOI PMC

Sala L., van Meer B.J., Tertoolen L.G.J., Bakkers J., Bellin M., Davis R.P., Denning C., Dieben M.A.E., Eschenhagen T., Giacomelli E., et al. MUSCLEMOTION: a versatile open software tool to quantify cardiomyocyte and cardiac muscle contraction in vitro and in vivo. Circ. Res. 2018;122:e5–e16. doi: 10.1161/CIRCRESAHA.117.312067. PubMed DOI PMC

Zheng G.X.Y., Terry J.M., Belgrader P., Ryvkin P., Bent Z.W., Wilson R., Ziraldo S.B., Wheeler T.D., McDermott G.P., Zhu J., et al. Massively parallel digital transcriptional profiling of single cells. Nat. Commun. 2017;8 doi: 10.1038/ncomms14049. PubMed DOI PMC

McCarthy D.J., Campbell K.R., Lun A.T.L., Wills Q.F. Scater: pre-processing, quality control, normalization and visualization of single-cell RNA-seq data in R. Bioinformatics. 2017;33:1179–1186. doi: 10.1093/bioinformatics/btw777. PubMed DOI PMC

Stuart T., Butler A., Hoffman P., Hafemeister C., Papalexi E., Mauck W.M., Hao Y., Stoeckius M., Smibert P., Satija R. Comprehensive integration of single-cell data. Cell. 2019;177:1888–1902.e21. doi: 10.1016/j.cell.2019.05.031. PubMed DOI PMC

Pages H.,C.M., Falcon S., Li N. AnnotationDbi: Manipulation of SQLite-based Annotations in Bioconductor. 2021. https://bioconductor.org/packages/AnnotationDbi R package version 1.54.0.

Yu G., Wang L.-G., Han Y., He Q.-Y. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS A J. Integr. Biol. 2012;16:284–287. doi: 10.1089/omi.2011.0118. PubMed DOI PMC

Kang J.X., Leaf A. Protective effects of All-trans-retinoic acid against cardiac arrhythmias induced by isoproterenol, lysophosphatidylcholine or ischemia and reperfusion. J. Cardiovasc. Pharmacol. 1995;26:943–948. PubMed

Cai W., Wang J., Hu M., Chen X., Lu Z., Bellanti J.A., Zheng S.G. All trans-retinoic acid protects against acute ischemic stroke by modulating neutrophil functions through STAT1 signaling. J. Neuroinflammation. 2019;16 doi: 10.1186/s12974-019-1557-6. PubMed DOI PMC

Weber K., Thomaschewski M., Benten D., Fehse B. RGB marking with lentiviral vectors for multicolor clonal cell tracking. Nat. Protoc. 2012;7:839–849. doi: 10.1038/nprot.2012.026. PubMed DOI

Wang J., Vasaikar S., Shi Z., Greer M., Zhang B. WebGestalt 2017: a more comprehensive, powerful, flexible and interactive gene set enrichment analysis toolkit. Nucleic Acids Res. 2017;45:W130–W137. doi: 10.1093/nar/gkx356. PubMed DOI PMC

Liu J., Ji H., Zheng W., Wu X., Zhu J.J., Arnold A.P., Sandberg K. Sex differences in renal angiotensin converting enzyme 2 (ACE2) activity are 17beta-oestradiol-dependent and sex chromosome-independent. Biol. Sex Differ. 2010;1:6. doi: 10.1186/2042-6410-1-6. PubMed DOI PMC

Xia J., Psychogios N., Young N., Wishart D.S. MetaboAnalyst: a web server for metabolomic data analysis and interpretation. Nucleic Acids Res. 2009;37:W652–W660. doi: 10.1093/nar/gkp356. PubMed DOI PMC

Macosko E.Z., Basu A., Satija R., Nemesh J., Shekhar K., Goldman M., Tirosh I., Bialas A.R., Kamitaki N., Martersteck E.M., et al. Highly parallel genome-wide expression profiling of individual cells using nanoliter droplets. Cell. 2015;161:1202–1214. doi: 10.1016/j.cell.2015.05.002. PubMed DOI PMC

See more in PubMed

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