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SIRT6 in Regulation of Mitochondrial Damage and Associated Cardiac Dysfunctions: A Possible Therapeutic Target for CVDs

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Abstract

Cardiovascular diseases (CVDs) can be described as a global health emergency imploring possible prevention strategies. Although the pathogenesis of CVDs has been extensively studied, the role of mitochondrial dysfunction in CVD development has yet to be investigated. Diabetic cardiomyopathy, ischemic-reperfusion injury, and heart failure are some of the CVDs resulting from mitochondrial dysfunction Recent evidence from the research states that any dysfunction of mitochondria has an impact on metabolic alteration, eventually causes the death of a healthy cell and therefore, progressively directing to the predisposition of disease. Cardiovascular research investigating the targets that both protect and treat mitochondrial damage will help reduce the risk and increase the quality of life of patients suffering from various CVDs. One such target, i.e., nuclear sirtuin SIRT6 is strongly associated with cardiac function. However, the link between mitochondrial dysfunction and SIRT6 concerning cardiovascular pathologies remains poorly understood. Although the Role of SIRT6 in skeletal muscles and cardiomyocytes through mitochondrial regulation has been well understood, its specific role in mitochondrial maintenance in cardiomyocytes is poorly determined. The review aims to explore the domain-specific function of SIRT6 in cardiomyocytes and is an effort to know how SIRT6, mitochondria, and CVDs are related.

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Data Availability

The data set analysed during the current study is referenced in the text and is publicly available at https://drive.google.com/drive/folders/1fxa3shg3sn6SkQc3D6n0p9sXwz4abPuL?usp=drive_link

Abbreviations

ABCA1:

ATP-binding cassette transporters A1

ABCG1:

ATP-binding cassette transporters G1

AIF:

Apoptosis-inducing factor

Akt/mTOR:

Protein kinase B (Akt) and mammalian target of rapamycin

AMI:

Acute myocardial infarction

AMPK:

Adenosine monophosphate-activated protein kinase

ANG-II:

Angiotensin II

ANT:

Adenine nucleotide translocase

Bcl-2:

B-cell lymphoma-2

CHD:

Coronary heart disease

CM:

Cardiomyopathy

CSE:

Cigarette smoking extract

CVDs:

Cardiovascular diseases

D-gal:

D-galactose

DRP1:

Dynamin-related protein 1

DSBs:

Double-strand breakage

EMT:

Epithelial-mesenchymal transition

FDL:

“Fluor-de-Lys” deacetylation

FIS1:

Fission protein 1

FOXO:

Forkhead box class O

GCN5:

General control non-repressed protein 5

GSIS:

Glucose-stimulated insulin secretion

H3K9:

Histone H3 lysine 9

HBECs:

Human bronchial-tracheal epithelial cells

HF:

Heart failure

HF-HS:

High-fat, high-sucrose

HIF1-α:

Hypoxia-inducible factor 1-alpha

HM p-type Loci:

Haploid mating

HO-1:

Heme oxygenase

hTERT:

Human telomerase reverse transcriptase

I/R injury:

Ischemia–reperfusion

IGF:

Insulin-like growth factor

IHD:

Ischemic heart disease

JAK2/STAT3:

Janus kinase 2/signal transducer and activator of transcription

JNK:

C-Jun N-terminal kinases

Keap l:

Kelch-like ECH-associated protein 1

KO:

Knockout

LDL:

Low-density lipoproteins

MFN1/2:

Mitofusin-1/2

MnSOD:

Manganese superoxide dismutase

mtDNA:

Mitochondrial DNA

mTORC2:

MTOR complex 2

NAD + :

Nicotinamide adenine dinucleotide

NADH:

Nicotinamide adenine dinucleotide

NADPH:

Nicotinamide adenine dinucleotide phosphate hydrogen

NF-kB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

Nkx3.2:

NK3 homeobox 2

NRCMs:

Neonatal rat cardiomyocytes

NRF1:

Nuclear respiratory factor 1

NRF2/:

Nuclear factor erythropoietin-2-related factor 2

PARP1:

Poly (ADP-ribose) polymerase 1

PCSK9:

Proprotein convertase subtilisin/kexin type 9

PDHE1α:

Pyruvate dehydrogenase E1 alpha

PDHK1:

Pyruvate dehydrogenase kinase-1

PDK:

Pyruvate dehydrogenase gene

PGC-1:

Gamma coactivator-1

PPAR:

Peroxisome proliferator-activated receptor

PT:

Permeability transition

ROS:

Reactive oxygen species

SD rats:

Sprague–Dawley

SIRT:

Sirtuin

SMC:

Smooth muscle cells

SOD2:

Superoxide dismutase 2

SREBPs:

Sterol regulatory element-binding proteins

T2DM:

Type 2 diabetes mellitus

t-BHP:

Tert-butyl hydroperoxide

TNFSF4:

Tumour necrosis factor superfamily member 4

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Acknowledgements

We thank Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India for providing access to the library and all other facilities.

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Authors and Affiliations

  1. Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education (MAHE), Manipal, Karnataka, 576104, India

    K. P. Divya, P. V. Anuranjana, Gautam Kumar, Fathima Beegum, Krupa Thankam George & K. Nandakumar

  2. Department of Pharmaceutical Sciences and Technology, Maharaja Ranjit Singh Punjab, Technical University, Bathinda, Punjab, 151005, India

    Navjot Kanwar

  3. School of Pharmacy, Sharda University, Greater Noida, Uttar Pradesh, 201310, India

    Gautam Kumar

  4. Department of Pharmacology, National Institute of Pharmaceutical Educations and Research, Hajipur, Bihar, 844102, India

    Nitesh Kumar

  5. Department of Pharmacology, All India Institute of Medical Sciences, Bathinda, Punjab, 151005, India

    Abhinav Kanwal

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Contributions

Authors Divya KP, Anu Ranjana PV, Krupa Thankam George, and Fathima Beegum Wrote the MS. Authors Gautam Kumar and Divya KP draw the diagrams. Authors Nawjot Kanwar, Nitesh Kumar, and Gautam Kumar reviewed and edited the MS. Authors K. Nandakumar and Abhinav Kanwal conceptualized the MS and did a final review of the MS.

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Divya, K.P., Kanwar, N., Anuranjana, P.V. et al. SIRT6 in Regulation of Mitochondrial Damage and Associated Cardiac Dysfunctions: A Possible Therapeutic Target for CVDs. Cardiovasc Toxicol 24, 598–621 (2024). https://doi.org/10.1007/s12012-024-09858-1

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