Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Cardiovascular Drugs and Therapy
Published in: Cardiovascular Drugs and Therapy 2/2024

Open Access 18-01-2023 | Epigenetics | Invited: Bscr Marshall Submissions

Cardiovascular Mechano-Epigenetics: Force-Dependent Regulation of Histone Modifications and Gene Regulation

Authors: Pamela Swiatlowska, Thomas Iskratsch

Published in: Cardiovascular Drugs and Therapy | Issue 2/2024

Login to get access

Abstract

The local mechanical microenvironment impacts on the cell behavior. In the cardiovascular system, cells in both the heart and the vessels are exposed to continuous blood flow, blood pressure, stretching forces, and changing extracellular matrix stiffness. The force-induced signals travel all the way to the nucleus regulating epigenetic changes such as chromatin dynamics and gene expression. Mechanical cues are needed at the very early stage for a faultless embryological development, while later in life, aberrant mechanical signaling can lead to a range of pathologies, including diverse cardiovascular diseases. Hence, an investigation of force-generated epigenetic alteration at different time scales is needed to understand fully the phenotypic changes in disease onset and progression. That being so, cardiovascular mechano-epigenetics emerges as an attractive field of study. Given the rapid advances in this emergent field of research, this short review aims to provide an analysis of the state of knowledge of force-induced epigenetic changes in the cardiovascular field.
Literature
1.
Waddington CH. Canalization of development and the inheritance of acquired characters. Nature. 1942;150:563–5.CrossRef
2.
Shi Y, Zhang H, Huang S, et al. Epigenetic regulation in cardiovascular disease: mechanisms and advances in clinical trials. Signal Transduct Target Ther. 2022;7(1):200.PubMedPubMedCentralCrossRef
3.
Warton K, Mahon KL, Samimi G. Methylated circulating tumor DNA in blood: power in cancer prognosis and response. Endocr Relat Cancer. 2016;23(3):R157–71.PubMedPubMedCentralCrossRef
4.
Kumagai T, Akagi T, Desmond JC, et al. Epigenetic regulation and molecular characterization of C/EBPalpha in pancreatic cancer cells. Int J Cancer. 2009;124(4):827–33.PubMedPubMedCentralCrossRef
5.
Jia H, Morris CD, Williams RM, Loring JF, Thomas EA. HDAC inhibition imparts beneficial transgenerational effects in Huntington’s disease mice via altered DNA and histone methylation. Proc Natl Acad Sci U S A. 2015;112(1):E56-64.PubMedCrossRef
6.
Abdolmaleky HM, Zhou JR, Thiagalingam S, Smith CL. Epigenetic and pharmacoepigenomic studies of major psychoses and potentials for therapeutics. Pharmacogenomics. 2008;9(12):1809–23.PubMedCrossRef
7.
Greer JM, McCombe PA. The role of epigenetic mechanisms and processes in autoimmune disorders. Biologics. 2012;6:307–27.PubMedPubMedCentral
8.
Iskratsch T, Wolfenson H, Sheetz MP. Appreciating force and shape-the rise of mechanotransduction in cell biology. Nat Rev Mol Cell Biol. 2014;15(12):825–33.PubMedPubMedCentralCrossRef
9.
Sit B, Gutmann D, Iskratsch T. Costameres, dense plaques and podosomes: the cell matrix adhesions in cardiovascular mechanosensing. J Muscle Res Cell Motil. 2019;40(2):197–209.PubMedPubMedCentralCrossRef
10.
Ward M, Iskratsch T. Mix and (mis-)match – The mechanosensing machinery in the changing environment of the developing, healthy adult and diseased heart. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 2020;1867(3):118436
11.
Lucitti JL, Jones EA, Huang C, Chen J, Fraser SE, Dickinson ME. Vascular remodeling of the mouse yolk sac requires hemodynamic force. Development. 2007;134(18):3317–26.PubMedCrossRef
12.
Swiatlowska P, Sit B, Feng Z, et al. Pressure and stiffness sensing together regulate vascular smooth muscle cell phenotype switching. Sci Adv. 2022;8(15):eabm3471.PubMedPubMedCentralCrossRef
13.
Bertillot F, Miroshnikova YA, Wickstrom SA. SnapShot: mechanotransduction in the nucleus. Cell. 2022;185(19):3638-e1.PubMedCrossRef
14.
Nava MM, Miroshnikova YA, Biggs LC, et al. Heterochromatin-driven nuclear softening protects the genome against mechanical stress-induced damage. Cell. 2020;181(4):800-17 e22.PubMedPubMedCentralCrossRef
15.
Liu L, Rodriguez-Mateo C, Huang P, et al. Hairless regulates heterochromatin maintenance and muscle stem cell function as a histone demethylase antagonist. Proc Natl Acad Sci U S A. 2021;118(37):e2025281118.
16.
Barnes CE, English DM, Cowley SM. Acetylation & Co: an expanding repertoire of histone acylations regulates chromatin and transcription. Essays Biochem. 2019;63(1):97–107.PubMedPubMedCentralCrossRef
17.
Koester J, Miroshnikova YA, Ghatak S, et al. Niche stiffening compromises hair follicle stem cell potential during ageing by reducing bivalent promoter accessibility. Nat Cell Biol. 2021;23(7):771–81.PubMedCrossRef
18.
Pundel OJ, Blowes LM, Connelly JT. Extracellular adhesive cues physically define nucleolar structure and function. Adv Sci (Weinh). 2022;9(10): e2105545.PubMedCrossRef
19.
Le HQ, Ghatak S, Yeung CY, et al. Mechanical regulation of transcription controls Polycomb-mediated gene silencing during lineage commitment. Nat Cell Biol. 2016;18(8):864–75.PubMedCrossRef
20.
21.
Song Y, Soto J, Chen B, et al. Transient nuclear deformation primes epigenetic state and promotes cell reprogramming. Nat Mater. 2022;21(10):1191–1199
22.
23.
He M, Huang TS, Li S, et al. Atheroprotective flow upregulates ITPR3 (Inositol 1,4,5-trisphosphate receptor 3) in vascular endothelium via KLF4 (Kruppel-like factor 4)-mediated histone modifications. Arterioscler Thromb Vasc Biol. 2019;39(5):902–14.PubMedPubMedCentralCrossRef
24.
Andueza A, Kumar S, Kim J, et al. Endothelial Reprogramming by disturbed flow revealed by single-cell RNA and chromatin accessibility study. Cell Rep. 2020;33(11): 108491.PubMedPubMedCentralCrossRef
25.
26.
Zeng L, Zhang Y, Chien S, Liu X, Shyy JY. The role of p53 deacetylation in p21Waf1 regulation by laminar flow. J Biol Chem. 2003;278(27):24594–9.PubMedCrossRef
27.
Zeng L, Xiao Q, Margariti A, et al. HDAC3 is crucial in shear- and VEGF-induced stem cell differentiation toward endothelial cells. J Cell Biol. 2006;174(7):1059–69.PubMedPubMedCentralCrossRef
28.
Lee DY, Lee CI, Lin TE, et al. Role of histone deacetylases in transcription factor regulation and cell cycle modulation in endothelial cells in response to disturbed flow. Proc Natl Acad Sci U S A. 2012;109(6):1967–72.PubMedPubMedCentralCrossRef
29.
Yan ZQ, Yao QP, Zhang ML, et al. Histone deacetylases modulate vascular smooth muscle cell migration induced by cyclic mechanical strain. J Biomech. 2009;42(7):945–8.PubMedCrossRef
30.
Wang YH, Yan ZQ, Qi YX, et al. Normal shear stress and vascular smooth muscle cells modulate migration of endothelial cells through histone deacetylase 6 activation and tubulin acetylation. Ann Biomed Eng. 2010;38(3):729–37.PubMedCrossRef
31.
Wang W, Ha CH, Jhun BS, Wong C, Jain MK, Jin ZG. Fluid shear stress stimulates phosphorylation-dependent nuclear export of HDAC5 and mediates expression of KLF2 and eNOS. Blood. 2010;115(14):2971–9.PubMedPubMedCentralCrossRef
32.
Elibol B, Kilic U. High Levels of SIRT1 Expression as a Protective mechanism against disease-related conditions. Front Endocrinol (Lausanne). 2018;9:614.PubMedCrossRef
33.
Kitada M, Ogura Y, Koya D. The protective role of Sirt1 in vascular tissue: its relationship to vascular aging and atherosclerosis. Aging (Albany NY). 2016;8(10):2290–307.PubMedCrossRef
34.
Yuan P, Hu Q, He X, et al. Laminar flow inhibits the Hippo/YAP pathway via autophagy and SIRT1-mediated deacetylation against atherosclerosis. Cell Death Dis. 2020;11(2):141.PubMedPubMedCentralCrossRef
35.
Chen W, Bacanamwo M, Harrison DG. Activation of p300 histone acetyltransferase activity is an early endothelial response to laminar shear stress and is essential for stimulation of endothelial nitric-oxide synthase mRNA transcription. J Biol Chem. 2008;283(24):16293–8.PubMedPubMedCentralCrossRef
36.
37.
Basatemur GL, Jorgensen HF, Clarke MCH, Bennett MR, Mallat Z. Vascular smooth muscle cells in atherosclerosis. Nat Rev Cardiol. 2019;16(12):727–44.PubMedCrossRef
38.
Newman AAC, Serbulea V, Baylis RA, et al. Multiple cell types contribute to the atherosclerotic lesion fibrous cap by PDGFRbeta and bioenergetic mechanisms. Nat Metab. 2021;3(2):166–81.PubMedPubMedCentralCrossRef
39.
Durham AL, Speer MY, Scatena M, Giachelli CM, Shanahan CM. Role of smooth muscle cells in vascular calcification: implications in atherosclerosis and arterial stiffness. Cardiovasc Res. 2018;114(4):590–600.PubMedPubMedCentralCrossRef
40.
Zurek M, Aavik E, Mallick R, Yla-Herttuala S. Epigenetic regulation of vascular smooth muscle cell phenotype switching in atherosclerotic artery remodeling: a mini-review. Front Genet. 2021;12: 719456.PubMedPubMedCentralCrossRef
41.
Liu M, Espinosa-Diez C, Mahan S, et al. H3K4 di-methylation governs smooth muscle lineage identity and promotes vascular homeostasis by restraining plasticity. Dev Cell. 2021;56(19):2765-82 e10.PubMedPubMedCentralCrossRef
42.
Kato N, Loh M, Takeuchi F, et al. Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation. Nat Genet. 2015;47(11):1282–93.PubMedPubMedCentralCrossRef
43.
Liu L, He F, Yu Y, Wang Y. Application of FRET Biosensors in Mechanobiology and Mechanopharmacological Screening. Front Bioeng Biotechnol. 2020;8: 595497.PubMedPubMedCentralCrossRef
44.
Finke D, Schanze LM, Schreiter F, et al. Histone deacetylase 4 deletion broadly affects cardiac epigenetic repression and regulates transcriptional susceptibility via H3K9 methylation. J Mol Cell Cardiol. 2022;162:119–29.PubMedCrossRef
45.
Mathiyalagan P, Keating ST, Du XJ, El-Osta A. Chromatin modifications remodel cardiac gene expression. Cardiovasc Res. 2014;103(1):7–16.PubMedCrossRef
46.
Seelbinder B, Ghosh S, Schneider SE, et al. Nuclear deformation guides chromatin reorganization in cardiac development and disease. Nat Biomed Eng. 2021;5(12):1500–16.PubMedPubMedCentralCrossRef
47.
Zhang CL, McKinsey TA, Chang S, Antos CL, Hill JA, Olson EN. Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy. Cell. 2002;110(4):479–88.PubMedPubMedCentralCrossRef
48.
Li G, Yang Q, Yang Y, et al. Laminar shear stress alters endothelial KCa2.3 expression in H9c2 cells partially via regulating the PI3K/Akt/p300 axis. Int J Mol Med. 2019;43(3):1289–98.PubMedPubMedCentral
49.
Swiatlowska P, Iskratsch T. Tools for studying and modulating (cardiac muscle) cell mechanics and mechanosensing across the scales. Biophys Rev. 2021;13(5):611–23.PubMedPubMedCentralCrossRef
50.
Ho JW, Bishop E, Karchenko PV, Negre N, White KP, Park PJ. ChIP-chip versus ChIP-seq: lessons for experimental design and data analysis. BMC Genomics. 2011;12:134.PubMedPubMedCentralCrossRef
51.
52.
Skene PJ, Henikoff JG, Henikoff S. Targeted in situ genome-wide profiling with high efficiency for low cell numbers. Nat Protoc. 2018;13(5):1006–19.PubMedCrossRef
53.
Verhelst S, De Clerck L, Willems S, et al. Comprehensive histone epigenetics: a mass spectrometry based screening assay to measure epigenetic toxicity. MethodsX. 2020;7: 101055.PubMedPubMedCentralCrossRef
54.
Sato Y, Nakao M, Kimura H. Live-cell imaging probes to track chromatin modification dynamics. Microscopy (Oxf). 2021;70(5):415–22.PubMedCrossRef
55.
Lin CW, Jao CY, Ting AY. Genetically encoded fluorescent reporters of histone methylation in living cells. J Am Chem Soc. 2004;126(19):5982–3.PubMedCrossRef
56.
Chu L, Zhu T, Liu X, et al. SUV39H1 orchestrates temporal dynamics of centromeric methylation essential for faithful chromosome segregation in mitosis. J Mol Cell Biol. 2012;4(5):331–40.PubMedPubMedCentralCrossRef
57.
Peng Q, Lu S, Shi Y, et al. Coordinated histone modifications and chromatin reorganization in a single cell revealed by FRET biosensors. Proc Natl Acad Sci U S A. 2018;115(50):E11681–90.PubMedPubMedCentralCrossRef
58.
59.
Ito T, Umehara T, Sasaki K, et al. Real-time imaging of histone H4K12-specific acetylation determines the modes of action of histone deacetylase and bromodomain inhibitors. Chem Biol. 2011;18(4):495–507.PubMedCrossRef
60.
Sasaki K, Ito T, Nishino N, Khochbin S, Yoshida M. Real-time imaging of histone H4 hyperacetylation in living cells. Proc Natl Acad Sci U S A. 2009;106(38):16257–62.PubMedPubMedCentralCrossRef
61.
Nakaoka S, Sasaki K, Ito A, Nakao Y, Yoshida M. A genetically encoded FRET probe to Detect intranucleosomal histone H3K9 or H3K14 acetylation using BRD4, a BET family member. ACS Chem Biol. 2016;11(3):729–33.PubMedCrossRef
62.
Sasaki K, Yoshida M. The exploitation of FRET probes to track bromodomain/histone interactions in cells for bromodomain inhibitors. Drug Discov Today Technol. 2016;19:51–6.PubMedCrossRef
63.
Lin CW, Ting AY. A genetically encoded fluorescent reporter of histone phosphorylation in living cells. Angew Chem Int Ed Engl. 2004;43(22):2940–3.PubMedCrossRef
64.
Raciti GA, Desiderio A, Longo M, et al. DNA methylation and type 2 diabetes: novel biomarkers for risk assessment? Int J Mol Sci. 2021;22(21):11652.
65.
Fathollahi A, Aslani S, Jamshidi A, Mahmoudi M. Epigenetics in osteoarthritis: novel spotlight. J Cell Physiol. 2019;234(8):12309–24.PubMedCrossRef
66.
Costa-Pinheiro P, Montezuma D, Henrique R, Jeronimo C. Diagnostic and prognostic epigenetic biomarkers in cancer. Epigenomics. 2015;7(6):1003–15.PubMedCrossRef
67.
68.
Shukla N, Wetmore C, O’Brien MM, et al. Final report of phase 1 study of the DOT1L inhibitor, pinometostat (EPZ-5676), in Children with Relapsed or Refractory MLL-r Acute Leukemia. Blood. 2016;22(128):2780.CrossRef
69.
Palamaris K, Moutafi M, Gakiopoulou H, Theocharis S. Histone deacetylase (HDAC) inhibitors: a Promising weapon to tackle therapy resistance in melanoma. Int J Mol Sci. 2022;23(7):3660.
70.
Yadav R, Mishra P, Yadav D. Histone deacetylase inhibitors: a prospect in drug discovery. Turk J Pharm Sci. 2019;16(1):101–14.PubMedCrossRef
71.
Han S, Uludag MO, Usanmaz SE, Ayaloglu-Butun F, Akcali KC, Demirel-Yilmaz E. Resveratrol affects histone 3 lysine 27 methylation of vessels and blood biomarkers in DOCA salt-induced hypertension. Mol Biol Rep. 2015;42(1):35–42.PubMedCrossRef
72.
Li SJ, Kao YH, Chung CC, Chen WY, Cheng WL, Chen YJ. Activated p300 acetyltransferase activity modulates aortic valvular calcification with osteogenic transdifferentiation and downregulation of Klotho. Int J Cardiol. 2017;232:271–9.PubMedCrossRef
73.
Tian S, Lei I, Gao W, et al. HDAC inhibitor valproic acid protects heart function through Foxm1 pathway after acute myocardial infarction. EBioMedicine. 2019;39:83–94.PubMedCrossRef
74.
Cardinale JP, Sriramula S, Pariaut R, et al. HDAC inhibition attenuates inflammatory, hypertrophic, and hypertensive responses in spontaneously hypertensive rats. Hypertension. 2010;56(3):437–44.PubMedCrossRef
75.
McKinsey TA, Foo R, Anene-Nzelu CG, et al. Emerging epigenetic therapies of cardiac fibrosis and remodeling in heart failure: from basic mechanisms to early clinical development. Cardiovasc Res. 2022;cvac142.
76.
Laggerbauer B, Engelhardt S. MicroRNAs as therapeutic targets in cardiovascular disease. J Clin Invest. 2022;132(11):e159179.
77.
Gallant-Behm CL, Piper J, Dickinson BA, Dalby CM, Pestano LA, Jackson AL. A synthetic microRNA-92a inhibitor (MRG-110) accelerates angiogenesis and wound healing in diabetic and nondiabetic wounds. Wound Repair Regen. 2018;26(4):311–23.PubMedCrossRef
78.
Guay SP, Legare C, Houde AA, Mathieu P, Bosse Y, Bouchard L. Acetylsalicylic acid, aging and coronary artery disease are associated with ABCA1 DNA methylation in men. Clin Epigenet. 2014;6(1):14.CrossRef
79.
Deng C, Lu Q, Zhang Z, et al. Hydralazine may induce autoimmunity by inhibiting extracellular signal-regulated kinase pathway signaling. Arthritis Rheum. 2002;3(48):746–56.
80.
Pushpakom S, Iorio F, Eyers PA, et al. Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov. 2019;18(1):41–58.PubMedCrossRef
81.
Swift J, Ivanovska IL, Buxboim A, et al. Nuclear lamin-A scales with tissue stiffness and enhances matrix-directed differentiation. Science. 2013;341(6149):1240104.PubMedPubMedCentralCrossRef
82.
Miroshnikova YA, Nava MM, Wickstrom SA. Emerging roles of mechanical forces in chromatin regulation. J Cell Sci. 2017;130(14):2243–50.PubMed
Metadata
Title
Cardiovascular Mechano-Epigenetics: Force-Dependent Regulation of Histone Modifications and Gene Regulation
Authors
Pamela Swiatlowska
Thomas Iskratsch
Publication date
18-01-2023
Publisher
Springer US
Keyword
Epigenetics
Published in
Cardiovascular Drugs and Therapy / Issue 2/2024
Print ISSN: 0920-3206
Electronic ISSN: 1573-7241
DOI
https://doi.org/10.1007/s10557-022-07422-z

Other articles of this Issue 2/2024

Cardiovascular Drugs and Therapy 2/2024 Go to the issue

Original Article

Machine Learning-Based Model for Predicting Prolonged Mechanical Ventilation in Patients with Congestive Heart Failure

Original Article

Canagliflozin Pretreatment Attenuates Myocardial Dysfunction and Improves Postcardiac Arrest Outcomes After Cardiac Arrest and Cardiopulmonary Resuscitation in Mice

Original Article

Association Between Platelet Glycoprotein IIb/IIIa Inhibition and In-Hospital Outcomes in ST-Elevation Myocardial Infarction Patients Treated with Coronary Thrombus Aspiration: Findings from the CCC-ACS Project

Original Article

Calsyntenin-1 Promotes Doxorubicin-induced Dilated Cardiomyopathy in Rats

Original Article

Circ_0026218 ameliorates oxidized low-density lipoprotein-induced vascular endothelial cell dysfunction by regulating miR-188-3p/TLR4/NF-κB pathway

Editorial

Improving STEMI Reperfusion with Intracoronary Thrombolysis: A Way to “Go with the Flow”

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits