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Toxicol Lett. 2016 Sep 6;258:134-146. doi: 10.1016/j.toxlet.2016.06.020. Epub 2016 Jun 21.

Zinc deficiency exacerbates while zinc supplement attenuates cardiac hypertrophy in high-fat diet-induced obese mice through modulating p38 MAPK-dependent signaling.

Author information

1
Cardiovascular Center, the First Hospital of Jilin University, Changchun, China; Department of Pediatrics, University of Louisville, Louisville, KY, USA.
2
Department of Pediatrics, University of Louisville, Louisville, KY, USA; Department of Nephrology, the Second Hospital of Jilin University, Changchun, China.
3
Department of Pediatrics, University of Louisville, Louisville, KY, USA.
4
Department of Pediatrics, University of Louisville, Louisville, KY, USA; Department of Internal Medicine, Marshall University Joan C. Edwards School of Medicine, Huntington, WV, USA.
5
Department of Pediatrics, University of Louisville, Louisville, KY, USA; Wendy Novak Diabetes Care Center, University of Louisville, Louisville, KY, USA.
6
Cardiovascular Center, the First Hospital of Jilin University, Changchun, China.
7
Department of Chemistry, University of Louisville, Louisville, KY, USA.
8
Cardiovascular Center, the First Hospital of Jilin University, Changchun, China. Electronic address: zhengyang@jlu.edu.cn.
9
Department of Pediatrics, University of Louisville, Louisville, KY, USA; Wendy Novak Diabetes Care Center, University of Louisville, Louisville, KY, USA. Electronic address: l0cai001@louisville.edu.

Abstract

Childhood obesity often leads to cardiovascular diseases, such as obesity-related cardiac hypertrophy (ORCH), in adulthood, due to chronic cardiac inflammation. Zinc is structurally and functionally essential for many transcription factors; however, its role in ORCH and underlying mechanism(s) remain unclear and were explored here in mice with obesity induced with high-fat diet (HFD). Four week old mice were fed on either HFD (60%kcal fat) or normal diet (ND, 10% kcal fat) for 3 or 6 months, respectively. Either diet contained one of three different zinc quantities: deficiency (ZD, 10mg zinc per 4057kcal), normal (ZN, 30mg zinc per 4057kcal) or supplement (ZS, 90mg zinc per 4057kcal). HFD induced a time-dependent obesity and ORCH, which was accompanied by increased cardiac inflammation and p38 MAPK activation. These effects were worsened by ZD in HFD/ZD mice and attenuated by ZS in HFD/ZS group, respectively. Also, administration of a p38 MAPK specific inhibitor in HFD mice for 3 months did not affect HFD-induced obesity, but completely abolished HFD-induced, and zinc deficiency-worsened, ORCH and cardiac inflammation. In vitro exposure of adult cardiomyocytes to palmitate induced cell hypertrophy accompanied by increased p38 MAPK activation, which was heightened by zinc depletion with its chelator TPEN. Inhibition of p38 MAPK with its specific siRNA also prevented the effects of palmitate on cardiomyocytes. These findings demonstrate that ZS alleviates but ZD heightens cardiac hypertrophy in HFD-induced obese mice through suppressing p38 MAPK-dependent cardiac inflammatory and hypertrophic pathways.

KEYWORDS:

Cardiac hypertrophy; Obesity; P38 MAPK; Zinc supplement

PMID:
27346292
DOI:
10.1016/j.toxlet.2016.06.020
[Indexed for MEDLINE]

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