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Pterostilbene Decreases Cardiac Oxidative Stress and Inflammation via Activation of AMPK/Nrf2/HO-1 Pathway in Fructose-Fed Diabetic Rats

Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Abstract

Purpose

Oxidative stress has a pivotal role in the pathogenesis of diabetes-associated cardiovascular problems, which has remained a primary cause of the increased morbidity and mortality in diabetic patients. It is of paramount importance to prevent the diabetes-associated cardiac complications by reducing oxidative stress with the help of nutritional or pharmacological agents. Pterostilbene (PT), the primary antioxidant in blueberries, has recently gained attention for its promising health benefits in metabolic and cardiac diseases. However, the mechanism whereby PT reduces diabetic cardiac complications is currently unknown.

Methods

Sprague-Dawley rats were fed with 65% fructose diet with or without PT (20 mg kg−1 day−1) for 8 weeks. Heart rate and blood pressure were measured by tail-cuff apparatus. Real-time PCR and western blot experiments were executed to quantify the expression levels of mRNA and protein, respectively.

Results

Fructose-fed rats demonstrated cardiac hypertrophy, hypertension, enhanced myocardial oxidative stress, inflammation and increased NF-κB expression. Administration of PT significantly decreased cardiac hypertrophy, hypertension, oxidative stress, inflammation, NF-κB expression and NLRP3 inflammasome. We demonstrated that PT improved mitochondrial biogenesis as evidenced by increased protein expression of PGC-1α, complex III and complex V in fructose-fed diabetic rats. Further, PT increased protein expressions of AMPK, Nrf2, HO-1 in cardiac tissues, which may account for the prevention of cardiac oxidative stress and inflammation in fructose-fed rats.

Conclusions

Collectively, PT reduced cardiac oxidative stress and inflammation in diabetic rats through stimulation of AMPK/Nrf2/HO-1 signalling.

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Abbreviations

PT:

Pterostilbene

AMPK:

5′ adenosine monophosphate-activated protein kinase

SOD:

Superoxide dismutase

GSH:

Reduced glutathione

GPx:

Glutathione peroxidase

ROS:

Reactive oxygen species

TBARS:

Thiobarbituric acid reactive substances

HO-1:

Heme-oxygenase

NF-κB:

Nuclear factor- κB

IL:

Interleukin

TNF-α:

Tumour necrosis factor-α

LDH:

Lactate dehydrogenase

CK-MB:

Creatine kinase-MB

AST:

Aspartate aminotransferase

MAP:

Mean arterial pressure

ELISA:

Enzyme-linked immunosorbent assay

PCR:

Polymerase chain reaction

PGC-1α:

Peroxisome proliferator-activated receptor gamma coactivator

Nrf2:

Nuclear factor erythroid 2–related factor 2

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

C:

Control

D:

Fructose-fed diabetic

NLRP3:

Nucleotide-binding oligomerisation domain-like receptor (NLR) protein 3

ASC:

The adapter protein apoptosis-associated speck-like protein containing caspase recruitment domain

TLR4:

Toll-like receptor 4

CC:

Compound C

TXNIP:

Thioredoxin-interacting protein.

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Acknowledgements

Ramoji Kosuru was supported by the Indian Institute of Technology (Banaras Hindu University), Varanasi for providing Teaching Assistantship funded by Ministry of Human Resource Development, Government of India. We gratefully acknowledge the Sami Labs Limited, Bangalore, India, for providing pterostilbene as a generous gift sample.

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Correspondence to Sanjay Singh.

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The current investigation was performed in agreement with the principles of the Guide for the Care and Use of Laboratory Animals, published by the National Institutes of Health (NIH publication no. 86–23, revised 1996), and the experiments were approved by the Institutional Animal Ethical Committee of Institute of Medical Sciences (IMS), Banaras Hindu University (BHU), Varanasi, India.

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Kosuru, R., Kandula, V., Rai, U. et al. Pterostilbene Decreases Cardiac Oxidative Stress and Inflammation via Activation of AMPK/Nrf2/HO-1 Pathway in Fructose-Fed Diabetic Rats. Cardiovasc Drugs Ther 32, 147–163 (2018). https://doi.org/10.1007/s10557-018-6780-3

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