Pterostilbene Decreases Cardiac Oxidative Stress and Inflammation via Activation of AMPK/Nrf2/HO-1 Pathway in Fructose-Fed Diabetic Rats
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.
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.
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.
Collectively, PT reduced cardiac oxidative stress and inflammation in diabetic rats through stimulation of AMPK/Nrf2/HO-1 signalling.
KeywordsAMPK Pterostilbene Nrf2 HO-1 Oxidative stress Inflammation NLRP3 inflammasome
5′ adenosine monophosphate-activated protein kinase
Reactive oxygen species
Thiobarbituric acid reactive substances
Nuclear factor- κB
Tumour necrosis factor-α
Mean arterial pressure
Enzyme-linked immunosorbent assay
Polymerase chain reaction
Peroxisome proliferator-activated receptor gamma coactivator
Nuclear factor erythroid 2–related factor 2
Glyceraldehyde 3-phosphate dehydrogenase
Nucleotide-binding oligomerisation domain-like receptor (NLR) protein 3
The adapter protein apoptosis-associated speck-like protein containing caspase recruitment domain
Toll-like receptor 4
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.
Compliance with Ethical Standards
Conflicts of Interest
The authors declare that they have no conflict of interest.
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.
This study was not a clinical research and therefore consent for participate was not needed.
Consent for Publication
All authors have approved the submission for publication of the work.
- 8.Axelsen LN, Lademann JB, Petersen JS, Holstein-Rathlou N-H, Ploug T, Prats C, et al. Cardiac and metabolic changes in long-term high fructose-fat fed rats with severe obesity and extensive intramyocardial lipid accumulation. Am J Physiol Regul Integr Comp Physiol. 2010;298(6):R1560–70.CrossRefPubMedGoogle Scholar
- 9.Mo C, Wang L, Zhang J, Numazawa S, Tang H, Tang X, et al. The crosstalk between Nrf2 and AMPK signal pathways is important for the anti-inflammatory effect of berberine in LPS-stimulated macrophages and endotoxin-shocked mice. Antioxid Redox Signal. 2014;20(4):574–88.CrossRefPubMedPubMedCentralGoogle Scholar
- 10.Liu XM, Peyton KJ, Shebib AR, Wang H, Korthuis RJ, Durante W. Activation of AMPK stimulates heme oxygenase-1 gene expression and human endothelial cell survival. Am J Phys Heart Circ Phys. 2011;300(1):H84–93.Google Scholar
- 18.Maity P, Bindu S, Dey S, Goyal M, Alam A, Pal C, et al. Indomethacin, a non-steroidal anti-inflammatory drug, develops gastropathy by inducing reactive oxygen species-mediated mitochondrial pathology and associated apoptosis in gastric mucosa: a novel role of mitochondrial aconitase oxidation. J Biol Chem. 2009;284(5):3058–68.CrossRefPubMedGoogle Scholar
- 31.Delbosc S, Paizanis E, Magous R, Araiz C, Dimo T, Cristol J-P, et al. Involvement of oxidative stress and NADPH oxidase activation in the development of cardiovascular complications in a model of insulin resistance, the fructose-fed rat. Atherosclerosis. 2005;179(1):43–9.CrossRefPubMedGoogle Scholar
- 51.Russell LK, Mansfield CM, Lehman JJ, Kovacs A, Courtois M, Saffitz JE, et al. Cardiac-specific induction of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha promotes mitochondrial biogenesis and reversible cardiomyopathy in a developmental stage-dependent manner. Circ Res. 2004;94(4):525–33.CrossRefPubMedGoogle Scholar
- 53.Kukidome D, Nishikawa T, Sonoda K, Imoto K, Fujisawa K, Yano M, et al. Activation of AMP-activated protein kinase reduces hyperglycemia-induced mitochondrial reactive oxygen species production and promotes mitochondrial biogenesis in human umbilical vein endothelial cells. Diabetes. 2006;55(1):120–7.CrossRefPubMedGoogle Scholar
- 55.Bouchard-Thomassin AA, Lachance D, Drolet MC, Couet J, Arsenault M. A high-fructose diet worsens eccentric left ventricular hypertrophy in experimental volume overload. Am J Phys Heart Circ Phys. 2011;300(1):H125–34.Google Scholar
- 56.Nigro D, Menotti F, Cento AS, Serpe L, Chiazza F, Dal Bello F, et al. Chronic administration of saturated fats and fructose differently affect SREBP activity resulting in different modulation of Nrf2 and Nlrp3 inflammasome pathways in mice liver. J Nutr Biochem. 2017;42:160–71.CrossRefPubMedGoogle Scholar