title: Aspalathin Protects the Heart against Hyperglycemia-Induced Oxidative Damage by Up-Regulating Nrf2 Expression.
abstract: Aspalathin (ASP) can protect H9c2 cardiomyocytes against high glucose (HG)-induced shifts in myocardial substrate preference, oxidative stress, and apoptosis. The protective mechanism of ASP remains unknown. However, as one of possible, it is well known that phytochemical flavonoids reduce oxidative stress via nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activation resulting in up-regulation of antioxidant genes and enzymes. Therefore, we hypothesized that ASP protects the myocardium against HG- and hyperglycemia-induced oxidative damage by up-regulatingNrf2expression in H9c2 cardiomyocytes and diabetic (db/db) mice, respectively. Using an oxidative stress RT² Profiler PCR array, ASP at a dose of 1 µM was demonstrated to protect H9c2 cardiomyocytes against HG-induced oxidative stress, but silencing ofNrf2abolished this protective response of ASP and exacerbated cardiomyocyte apoptosis.Db/dbmice and their non-diabetic (db/+) littermate controls were subsequently treated daily for six weeks with either a low (13 mg/kg) or high (130 mg/kg) ASP dose. Compared to nondiabetic mice thedb/dbmice presented increased cardiac remodeling and enlarged left ventricular wall that occurred concomitant to enhanced oxidative stress. Daily treatment of mice with ASP at a dose of 130 mg/kg for six weeks was more effective at reversing complications than both a low dose ASP or metformin, eliciting enhanced expression ofNrf2and its downstream antioxidant genes. These results indicate that ASP maintains cellular homeostasis and protects the myocardium against hyperglycemia-induced oxidative stress through activation ofNrf2and its downstream target genes.
authors.affiliation: Biomedical Research and Innovation Platform (BRIP), Medical Research Council (MRC), Tygerberg 7505, South Africa. pdludla@mrc.ac.za.|Division of Medical Physiology, Faculty of Health Sciences, Stellenbosch University, Tygerberg 7505, South Africa. pdludla@mrc.ac.za.
authors.forename: Phiwayinkosi V
authors.initials: PV
authors.lastname: Dludla
authors.affiliation: Biomedical Research and Innovation Platform (BRIP), Medical Research Council (MRC), Tygerberg 7505, South Africa. christo.muller@mrc.ac.za.|Division of Medical Physiology, Faculty of Health Sciences, Stellenbosch University, Tygerberg 7505, South Africa. christo.muller@mrc.ac.za.|Department of Biochemistry and Microbiology, University of Zululand, Kwadlangezwa 3886, South Africa. christo.muller@mrc.ac.za.
authors.forename: Christo J F
authors.initials: CJ
authors.lastname: Muller
authors.affiliation: Post-Harvest and Wine Technology Division, Agricultural Research Council (ARC) Infruitec-Nietvoorbij, Stellenbosch 7599, South Africa. JoubertL@arc.agric.za.|Department of Food Science, Stellenbosch University, Stellenbosch 7599, South Africa. JoubertL@arc.agric.za.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Joubert
authors.affiliation: Biomedical Research and Innovation Platform (BRIP), Medical Research Council (MRC), Tygerberg 7505, South Africa. johan.louw@mrc.ac.za.|Department of Biochemistry and Microbiology, University of Zululand, Kwadlangezwa 3886, South Africa. johan.louw@mrc.ac.za.
authors.forename: Johan
authors.initials: J
authors.lastname: Louw
authors.affiliation: Cardio-Metabolic Research Group (CMRG), Department of Physiological Sciences, Stellenbosch University, Stellenbosch 7599, South Africa. mfessop@sun.ac.za.
authors.forename: M Faadiel
authors.initials: MF
authors.lastname: Essop
authors.affiliation: Biomedical Research and Innovation Platform (BRIP), Medical Research Council (MRC), Tygerberg 7505, South Africa. kwazi.gabuza@mrc.ac.za.
authors.forename: Kwazi B
authors.initials: KB
authors.lastname: Gabuza
authors.affiliation: Biomedical Research and Innovation Platform (BRIP), Medical Research Council (MRC), Tygerberg 7505, South Africa. samira.ghoor@mrc.ac.za.
authors.forename: Samira
authors.initials: S
authors.lastname: Ghoor
authors.affiliation: Biomedical Research and Innovation Platform (BRIP), Medical Research Council (MRC), Tygerberg 7505, South Africa. bh3@sun.ac.za.|Division of Medical Physiology, Faculty of Health Sciences, Stellenbosch University, Tygerberg 7505, South Africa. bh3@sun.ac.za.
authors.forename: Barbara
authors.initials: B
authors.lastname: Huisamen
authors.affiliation: Biomedical Research and Innovation Platform (BRIP), Medical Research Council (MRC), Tygerberg 7505, South Africa. rabia.johnson@mrc.ac.za.|Division of Medical Physiology, Faculty of Health Sciences, Stellenbosch University, Tygerberg 7505, South Africa. rabia.johnson@mrc.ac.za.
authors.forename: Rabia
authors.initials: R
authors.lastname: Johnson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002460:Cell Line; D047188:Chalcones / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004334:Drug Administration Schedule; D005786:Gene Expression Regulation; D005947:Glucose / Q000037:antagonists & inhibitors / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D002316:Cardiotonic Agents; D047188:Chalcones; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C495637:Nfe2l2 protein, rat; D034741:RNA, Small Interfering; C517016:aspalathin; D005947:Glucose
keywords: Nrf2; aspalathin; cardiomyopathy; diabetes mellitus; hyperglycemia; oxidative stress