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Sirtuin 7 ameliorates cuproptosis, myocardial remodeling and heart dysfunction in hypertension through the modulation of YAP/ATP7A signaling

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Abstract

Myocardial fibrosis is a typical pathological manifestation of hypertension. However, the exact role of sirtuin 7 (SIRT7) in myocardial remodeling remains largely unclear. Here, spontaneously hypertensive rats (SHRs) and angiotensin (Ang) II-induced hypertensive mice were pretreated with recombinant adeno-associated virus (rAAV)-SIRT7, copper chelator tetrathiomolybdate (TTM) or copper ionophore elesclomol, respectively. Compared with normotensive controls, reduced SIRT7 expression and augmented cuproptosis were observed in hearts of hypertensive rats and mice with decreased FDX1 levels and increased HSP70 levels. Notably, intervention with rAAV-SIRT7 and TTM strikingly prevented DLAT oligomers aggregation, and elevated ATP7A and TOM20 expressions, contributing to the alleviation of cuproptosis, mitochondrial injury, myocardial remodeling and heart dysfunction in spontaneously hypertensive rats and Ang II-induced hypertensive mice. In cultured rat primary cardiac fibroblasts (CFs), rhSIRT7 alleviated CuCl2, Ang II or elesclomol-induced cuproptosis and fibroblast activation by blunting DLAT oligomers accumulation and downregulating α-SMA expression. Additionally, conditioned medium from rhSIRT7-pretreated CFs remarkably mitigated cellular hypertrophy and mitochondrial impairments of neonatal rat cardiomyocytes, as well as cell migration and polarization of RAW 264.7 macrophages. Importantly, verteporfin reduced CuCl2-induced cuproptosis, mitochondrial injury and fibrotic activation in CFs. Knockdown of ATP7A with si-ATP7A blocked cellular protective effects of rhSIRT7 and verteporfin in CFs. In conclusion, SIRT7 attenuates cuproptosis, myocardial fibrosis and heart dysfunction in hypertension through the modulation of YAP/ATP7A signaling. Targeting SIRT7 is of vital importance for developing therapeutic strategies in hypertension and hypertensive heart disorders.

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Data availability

No datasets were generated or analysed during the current study.

Abbreviations

ANP:

Natriuretic peptide A

ATP7A:

ATPase copper transporting alpha

ATP7B:

ATPase copper transporting beta

BNP:

natriuretic peptide B

BSA:

Bovine serum albumin

BW:

Body weight

CCK-8:

Cell Counting kit-8

CF:

Cardiac fibroblast

Con:

Control

CTGF:

Connective tissue growth factor

CTR1:

Copper transporter 1

Cu:

Copper

DAPI:

4’,6-diamidino-2-phenylindole

DLAT:

Dihydrolipoamide s-acetyltransferase

DRP1:

Dynamin-related protein 1

EF:

Ejection fraction

ES:

Elesclomol

FDX1:

Ferredoxin 1

FS:

Fractional shortening

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

HE:

Hematoxylin and eosin

HSP70:

Heat shock protein 70

HW:

Heart weight

IL-1β:

Interleukin-1β

IL-6:

Interleukin-6

MFN2:

Mitofusin 2

MMP2:

Matrix metallopeptidase 2

MMP9:

Matrix metallopeptidase 9

MPTP:

Mitochondrial permeability transition pore

NAD+ :

Nicotinamide adenine dinucleotide

NRCM:

Neonatal rat cardiomyocytes

PMSF:

Phenylmethylsulfonyl fluoride

rAAV:

Recombinant adeno-associated virus

rhSIRT7:

recombinant human sirtuin 7

RIPA:

Radio-immunoprecipitation assay

ROS:

Reactive oxygen species

SHR:

Spontaneously hypertensive rat

siRNA:

small interfering RNA

si-NC:

siRNA negative control

SIRT:

Sirtuin

TEM:

Transmission electron microscopy

TL:

Tibia length

TNF-α:

Tumor necrosis factor-alpha

TOM20:

Translocase of outer mitochondrial membrane 20

TTM:

Tetrathiomolybdate

W:

Week

WGA:

Wheat germ agglutinin

WKY:

Wistar-Kyoto rat

YAP:

Yes-associated protein

α-SMA:

alpha-smooth muscle actin

β-MHC:

beta-myosin heavy chain

References

  1. Drazner MH (2011) The progression of hypertensive heart disease. Circulation 123:327–334. https://doi.org/10.1161/circulationaha.108.845792

    Article  PubMed  Google Scholar 

  2. Li J, Wang SY, Yan KX et al (2024) Intestinal microbiota by angiotensin receptor blocker therapy exerts protective effects against hypertensive damages. iMeta 3:e222. https://doi.org/10.1002/imt2.222

    Article  PubMed  PubMed Central  Google Scholar 

  3. Sauve AA, Youn DY (2012) Sirtuins: NAD(+)-dependent deacetylase mechanism and regulation. Curr Opin Chem Biol 16:535–543. https://doi.org/10.1016/j.cbpa.2012.10.003

    Article  PubMed  CAS  Google Scholar 

  4. Li XT, Zhang YP, Zhang MW, Zhang ZZ, Zhong JC (2022) Sirtuin 7 serves as a promising therapeutic target for cardiorenal diseases. Eur J Pharmacol 925. https://doi.org/10.1016/j.ejphar.2022.174977

  5. Winnik S, Auwerx J, Sinclair DA, Matter CM (2015) Protective effects of sirtuins in cardiovascular diseases: from bench to bedside. Eur Heart J 36:3404–3412. https://doi.org/10.1093/eurheartj/ehv290

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Li XT, Song JW, Zhang ZZ et al (2022) Sirtuin 7 mitigates renal ferroptosis, fibrosis and injury in hypertensive mice by facilitating the KLF15/Nrf2 signaling. Free Radic Biol Med 193:459–473. https://doi.org/10.1016/j.freeradbiomed.2022.10.320

    Article  PubMed  CAS  Google Scholar 

  7. Garoffolo G, Casaburo M, Amadeo F et al (2022) Reduction of Cardiac Fibrosis by Interference with YAP-Dependent Transactivation. Circul Res 131:239–257. https://doi.org/10.1161/circresaha.121.319373

    Article  CAS  Google Scholar 

  8. Mia MM, Cibi DM, Ghani S et al (2022) Loss of Yap/Taz in cardiac fibroblasts attenuates adverse remodelling and improves cardiac function. Cardiovascular Res 118:1785–1804. https://doi.org/10.1093/cvr/cvab205

    Article  CAS  Google Scholar 

  9. Mia MM, Cibi DM, Abdul Ghani SAB et al (2020) YAP/TAZ deficiency reprograms macrophage phenotype and improves infarct healing and cardiac function after myocardial infarction. PLoS Biol 18:e3000941. https://doi.org/10.1371/journal.pbio.3000941

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Kashihara T, Mukai R, Oka SI et al (2022) YAP mediates compensatory cardiac hypertrophy through aerobic glycolysis in response to pressure overload. J Clin Invest 132. https://doi.org/10.1172/jci150595

    Article  Google Scholar 

  11. Chowdhury K, Huang M, Kim HG, Dong XC (2022) Sirtuin 6 protects against hepatic fibrogenesis by suppressing the YAP and TAZ function. FASEB Journal: Official Publication Federation Am Soc Experimental Biology 36:e22529. https://doi.org/10.1096/fj.202200522R

    Article  CAS  Google Scholar 

  12. Yuan P, Hu Q, He X et al (2020) Laminar flow inhibits the Hippo/YAP pathway via autophagy and SIRT1-mediated deacetylation against atherosclerosis. Cell Death Dis 11:141. https://doi.org/10.1038/s41419-020-2343-1

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Chen L, Min J, Wang F (2022) Copper homeostasis and cuproptosis in health and disease. Signal Transduct Target Therapy 7. https://doi.org/10.1038/s41392-022-01229-y.:378.

  14. Yang L, Yang P, Lip GYH, Ren J (2023) Copper homeostasis and cuproptosis in cardiovascular disease therapeutics. Trends Pharmacol Sci 44:573–585. https://doi.org/10.1016/j.tips.2023.07.004

    Article  PubMed  CAS  Google Scholar 

  15. He P, Li H, Liu C et al (2022) U-shaped association between dietary copper intake and new-onset hypertension. Clin Nutr 41:536–542. https://doi.org/10.1016/j.clnu.2021.12.037

    Article  PubMed  CAS  Google Scholar 

  16. Darroudi S, Saberi-Karimian M, Tayefi M et al (2019) Association between Hypertension in healthy participants and zinc and copper status: a Population-based study. Biol Trace Elem Res 190:38–44. https://doi.org/10.1007/s12011-018-1518-4

    Article  PubMed  CAS  Google Scholar 

  17. Tsvetkov P, Coy S, Petrova B et al (2022) Copper induces cell death by targeting lipoylated TCA cycle proteins. Sci (New York NY) 375:1254–1261. https://doi.org/10.1126/science.abf0529

    Article  CAS  Google Scholar 

  18. Huo S, Wang Q, Shi W et al (2023) ATF3/SPI1/SLC31A1 signaling promotes Cuproptosis Induced by Advanced Glycosylation End products in Diabetic Myocardial Injury. Int J Mol Sci 24. https://doi.org/10.3390/ijms24021667

    Article  Google Scholar 

  19. Bian R, Wang Y, Li Z, Xu X (2023) Identification of cuproptosis-related biomarkers in dilated cardiomyopathy and potential therapeutic prediction of herbal medicines. Front Mol Biosci. https://doi.org/10.3389/fmolb.2023.1154920

    Article  PubMed  PubMed Central  Google Scholar 

  20. Song J, Ren K, Zhang D et al (2023) A novel signature combing cuproptosis- and ferroptosis-related genes in sepsis-induced cardiomyopathy. Front Genet 14:1170737. https://doi.org/10.3389/fgene.2023.1170737

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Yan J, Li Z, Li Y, Zhang Y (2024) Sepsis induced cardiotoxicity by promoting cardiomyocyte cuproptosis. Biochem Biophys Res Commun 690. https://doi.org/10.1016/j.bbrc.2023.149245.:149245.

  22. Yang M, Wang Y, He L, Shi X, Huang S (2024) Comprehensive bioinformatics analysis reveals the role of cuproptosis-related gene Ube2d3 in myocardial infarction. Front Immunol 15:1353111. https://doi.org/10.3389/fimmu.2024.1353111

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Chen N, Guo L, Wang L, Dai S, Zhu X, Wang E (2024) Sleep fragmentation exacerbates myocardial ischemia–reperfusion injury by promoting copper overload in cardiomyocytes. Nat Commun 15:3834. https://doi.org/10.1038/s41467-024-48227-y

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Davis J, Molkentin JD (2014) Myofibroblasts: trust your heart and let fate decide. J Mol Cell Cardiol 70:9–18. https://doi.org/10.1016/j.yjmcc.2013.10.019

    Article  PubMed  CAS  Google Scholar 

  25. Lee TM, Harn HJ, Chiou TW et al (2019) Remote transplantation of human adipose-derived stem cells induces regression of cardiac hypertrophy by regulating the macrophage polarization in spontaneously hypertensive rats. Redox Biol 27:101170. https://doi.org/10.1016/j.redox.2019.101170

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Wyman AE, Noor Z, Fishelevich R et al (2017) Sirtuin 7 is decreased in pulmonary fibrosis and regulates the fibrotic phenotype of lung fibroblasts. Am J Physiol Lung Cell Mol Physiol 312:L945. https://doi.org/10.1152/ajplung.00473.2016

    Article  PubMed  PubMed Central  Google Scholar 

  27. Yamamura S, Izumiya Y, Araki S et al (2020) Cardiomyocyte Sirt (Sirtuin) 7 Ameliorates Stress-Induced Cardiac Hypertrophy by Interacting With and Deacetylating GATA4. Hypertension (Dallas, Tex: 1979) 75:98–108.https://doi.org/10.1161/hypertensionaha.119.13357

  28. Vakhrusheva O, Smolka C, Gajawada P et al (2008) Sirt7 increases stress resistance of cardiomyocytes and prevents apoptosis and inflammatory cardiomyopathy in mice. Circul Res 102:703–710. https://doi.org/10.1161/circresaha.107.164558

    Article  CAS  Google Scholar 

  29. Araki S, Izumiya Y, Rokutanda T et al (2015) Sirt7 contributes to myocardial tissue repair by maintaining transforming growth Factor-β signaling pathway. Circulation 132:1081–1093. https://doi.org/10.1161/circulationaha.114.014821

    Article  PubMed  CAS  Google Scholar 

  30. Brilla CG, Reams GP, Maisch B, Weber KT (1993) Renin-angiotensin system and myocardial fibrosis in hypertension: regulation of the myocardial collagen matrix. Eur Heart J 14 Suppl J:57–61

  31. Lv SL, Zeng ZF, Gan WQ et al (2021) Lp-PLA2 inhibition prevents Ang II-induced cardiac inflammation and fibrosis by blocking macrophage NLRP3 inflammasome activation. Acta Pharmacol Sin 42:2016–2032. https://doi.org/10.1038/s41401-021-00703-7

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Wang D, Tian Z, Zhang P et al (2023) The molecular mechanisms of cuproptosis and its relevance to cardiovascular disease. Biomed Pharmacother 163:114830. https://doi.org/10.1016/j.biopha.2023.114830

    Article  PubMed  CAS  Google Scholar 

  33. Sonn SK, Song EJ, Seo S et al (2022) Peroxiredoxin 3 deficiency induces cardiac hypertrophy and dysfunction by impaired mitochondrial quality control. Redox Biol 51:102275. https://doi.org/10.1016/j.redox.2022.102275

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Ryu D, Jo YS, Lo Sasso G et al (2014) A SIRT7-dependent acetylation switch of GABPβ1 controls mitochondrial function. Cell Metabol 20:856–869. https://doi.org/10.1016/j.cmet.2014.08.001

    Article  CAS  Google Scholar 

Download references

Funding

This study was supported by the General Program and the National Major Research Plan Training Program of the National Natural Science Foundation of China (No. 82370432, 92168117) and Beijing Natural Science Foundation (7222068), Clinical Research Incubation Program of Beijing Chaoyang Hospital Affiliated to Capital Medical University (CYFH202209) and the 2025 Reform and Development Program of Beijing Institute of Respiratory Medicine (Ggyfz202502).

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Author notes

  1. Yu-Fei Chen and Rui-Qiang Qi contributed equally to this work.

Authors and Affiliations

  1. Heart Center and Beijing Key Laboratory of Hypertension, Beijing Institute of Respiratory Medicine and Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China

    Yu-Fei Chen, Rui-Qiang Qi, Jia-Wei Song, Si-Yuan Wang, Yi-Hang Chen, Ying Liu, Xin-Yu Zhou, Jing Li, Xiao-Yan Liu & Jiu-Chang Zhong

  2. Department of Cardiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China

    Yu-Fei Chen, Rui-Qiang Qi, Jia-Wei Song, Si-Yuan Wang, Zhao-Jie Dong, Ying Liu, Xin-Yu Zhou & Jiu-Chang Zhong

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Contributions

Yu-Fei Chen: Project administration, Data curation, Methodology, Writing – original draft. Rui-Qiang Qi: Formal analysis, Data curation, Visualization, Writing – original draft. Jia-Wei Song: Investigation, Conceptualization, Methodology. Si-Yuan Wang: Investigation, Conceptualization. Zhao-Jie Dong: Conceptualization, Methodology. Yi-Hang Chen: Formal analysis, Software. Ying Liu: Conceptualization, Software. Xin-Yu Zhou: Methodology, Visualization. Jing Li: Methodology, Supervision. Xiao-Yan Liu: Validation, Supervision. Jiu-Chang Zhong: Investigation, Formal analysis, Funding acquisition, Writing – review & editing.

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Correspondence to Jiu-Chang Zhong.

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Chen, YF., Qi, RQ., Song, JW. et al. Sirtuin 7 ameliorates cuproptosis, myocardial remodeling and heart dysfunction in hypertension through the modulation of YAP/ATP7A signaling. Apoptosis 29, 2161–2182 (2024). https://doi.org/10.1007/s10495-024-02021-9

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