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Silencing Survivin: a Key Therapeutic Strategy for Cardiac Hypertrophy

Abstract

Cardiac hypertrophy, in its aspects of localized thickening of the interventricular septum and concentric increase of the left ventricle, constitutes a risk factor of heart failure. Myocardial hypertrophy, in the presence of different degree of myocardial fibrosis, is paralleled by significant molecular, cellular, and histological changes inducing alteration of cardiac extracellular matrix composition as well as sarcomeres and cytoskeleton remodeling. Previous studies indicate osteopontin (OPN) and more recently survivin (SURV) overexpression as the hallmarks of heart failure although SURV function in the heart is not completely clarified. In this study, we investigated the involvement of SURV in intracellular signaling of hypertrophic cardiomyocytes and the impact of its transcriptional silencing, laying the foundation for novel target gene therapy in cardiac hypertrophy. Oligonucleotide-based molecules, like theranostic optical nanosensors (molecular beacons) and siRNAs, targeting SURV and OPN mRNAs, were developed. Their diagnostic and therapeutic potential was evaluated in vitro in hypertrophic FGF23-induced human cardiomyocytes and in vivo in transverse aortic constriction hypertrophic mouse model. Engineered erythrocyte was used as shuttle to selectively target and transfer siRNA molecules into unhealthy cardiac cells in vivo. The results highlight how the SURV knockdown could negatively influence the expression of genes involved in myocardial fibrosis in vitro and restores structural, functional, and morphometric features in vivo. Together, these data suggested that SURV is a key factor in inducing cardiomyocytes hypertrophy, and its shutdown is crucial in slowing disease progression as well as reversing cardiac hypertrophy. In the perspective, targeted delivery of siRNAs through engineered erythrocytes can represent a promising therapeutic strategy to treat cardiac hypertrophy.

Graphical abstract

Theranostic SURV molecular beacon (MB-SURV), transfected into FGF23-induced hypertrophic human cardiomyocytes, significantly dampened SURV overexpression. SURV down–regulation determines the tuning down of MMP9, TIMP1 and TIMP4 extracellular matrix remodeling factors while induces the overexpression of the cardioprotective MCAD factor, which counterbalance the absence of pro-survival and anti-apoptotic SURV activity to protect cardiomyocytes from death. In transverse aortic constriction (TAC) mouse model, the SURV silencing restores the LV mass levels to values not different from the sham group and counteracts the progressive decline of EF, maintaining its values always higher with respect to TAC group. These data demonstrate the central role of SURV in the cardiac reverse remodeling and its therapeutic potential to reverse cardiac hypertrophy.

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Abbreviations

ANP:

Atrial natriuretic peptide

BBQ:

Blackberry Quencher 650

β-MHC:

Beta- myosin heavy chain

BNP:

Brain natriuretic peptide

CLSM:

Confocal laser scanning microscopy

CSA:

Cross-sectional area

EF:

Ejection fraction

EGR1:

Early growth response 1

EMHV:

Erythro-Magneto-Ha virosome

ERK:

Extracellular signal-regulated kinases

FGF23:

Fibroblast growth factor 23

FHA:

Filamentous hemagglutinin

FS:

Fractional shortening

GADPH:

Glyceraldehyde-3-phosphate dehydrogenase

HCM:

Human cardiomyocyte

HF:

Heart failure

HRP:

Horseradish peroxidase

HW:

Heart weight

IHC:

Immunohistochemistry

IVSTd :

Interventricular septum thickness, diastolic

LC:

Left carotid

LV:

Left ventricle

LVAD:

Left ventricular assist device

LVPWTd :

Left ventricle posterior wall thickness, diastolic

MB:

Molecular beacon

MCAD:

Medium-chain acyl-CoA dehydrogenase

MMP:

Matrix metalloproteinase

NO:

Nitric oxide

NOX4:

NADPH oxidase 4

OPN:

Osteopontin

PFS:

Pixel fluorescence signal

RC:

Right carotid

sk-α-actin:

Skeletal-alpha-actin

SPION:

Super-paramagnetic iron oxide nanoparticles

SURV:

Survivin

TAC:

Transverse aortic constriction

TIMP:

Tissue inhibitor of metalloproteinase

TL:

Tibia length

UHFUS:

Ultra high-frequency ultrasound

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Acknowledgements

The authors thank Dr. Silvia Burchielli for supporting animal protocol preparation and internal ethical committee.

Funding

This work was supported by National Flagship project NANOMAX-ENCODER of the Italian Ministry of Education, University and Research.

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Correspondence to Maria Giovanna Trivella or Caterina Cinti.

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Kusmic, C., Vizzoca, A., Taranta, M. et al. Silencing Survivin: a Key Therapeutic Strategy for Cardiac Hypertrophy. J. of Cardiovasc. Trans. Res. (2021). https://doi.org/10.1007/s12265-021-10165-1

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Keywords

  • Cardiac hypertrophy
  • Target therapy
  • Surviving
  • Erythrocyte-based drug delivery system