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

Shudong Wang, Manyu Luo, Zhiguo Zhang, Junlian Gu, Jing Chen, Kristen Mc Clung Payne, Yi Tan, Yuehui Wang, Xia Yin, Xiang Zhang, Gilbert C. Liu, Kupper Wintergerst, Quan Liu, Yang Zheng, Lu Cai

Research output: Contribution to journalArticle

15 Citations (Scopus)

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, 10 mg zinc per 4057 kcal), normal (ZN, 30 mg zinc per 4057 kcal) or supplement (ZS, 90 mg zinc per 4057 kcal). 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.

Original languageEnglish (US)
Pages (from-to)134-146
Number of pages13
JournalToxicology Letters
Volume258
DOIs
StatePublished - Sep 6 2016
Externally publishedYes

Fingerprint

Obese Mice
Cardiomegaly
High Fat Diet
p38 Mitogen-Activated Protein Kinases
Nutrition
Zinc
Fats
Obesity
Palmitates
Inflammation
Cardiac Myocytes
Diet
Chemical activation
Pediatric Obesity
Chelating Agents
Hypertrophy
Small Interfering RNA
Transcription Factors
Cardiovascular Diseases

Keywords

  • Cardiac hypertrophy
  • Obesity
  • P38 MAPK
  • Zinc supplement

ASJC Scopus subject areas

  • Toxicology

Cite this

Zinc deficiency exacerbates while zinc supplement attenuates cardiac hypertrophy in high-fat diet-induced obese mice through modulating p38 MAPK-dependent signaling. / Wang, Shudong; Luo, Manyu; Zhang, Zhiguo; Gu, Junlian; Chen, Jing; Payne, Kristen Mc Clung; Tan, Yi; Wang, Yuehui; Yin, Xia; Zhang, Xiang; Liu, Gilbert C.; Wintergerst, Kupper; Liu, Quan; Zheng, Yang; Cai, Lu.

In: Toxicology Letters, Vol. 258, 06.09.2016, p. 134-146.

Research output: Contribution to journalArticle

Wang, S, Luo, M, Zhang, Z, Gu, J, Chen, J, Payne, KMC, Tan, Y, Wang, Y, Yin, X, Zhang, X, Liu, GC, Wintergerst, K, Liu, Q, Zheng, Y & Cai, L 2016, 'Zinc deficiency exacerbates while zinc supplement attenuates cardiac hypertrophy in high-fat diet-induced obese mice through modulating p38 MAPK-dependent signaling', Toxicology Letters, vol. 258, pp. 134-146. https://doi.org/10.1016/j.toxlet.2016.06.020
Wang, Shudong ; Luo, Manyu ; Zhang, Zhiguo ; Gu, Junlian ; Chen, Jing ; Payne, Kristen Mc Clung ; Tan, Yi ; Wang, Yuehui ; Yin, Xia ; Zhang, Xiang ; Liu, Gilbert C. ; Wintergerst, Kupper ; Liu, Quan ; Zheng, Yang ; Cai, Lu. / Zinc deficiency exacerbates while zinc supplement attenuates cardiac hypertrophy in high-fat diet-induced obese mice through modulating p38 MAPK-dependent signaling. In: Toxicology Letters. 2016 ; Vol. 258. pp. 134-146.
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AU - Gu, Junlian

AU - Chen, Jing

AU - Payne, Kristen Mc Clung

AU - Tan, Yi

AU - Wang, Yuehui

AU - Yin, Xia

AU - Zhang, Xiang

AU - Liu, Gilbert C.

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AU - Liu, Quan

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AU - Cai, Lu

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N2 - 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, 10 mg zinc per 4057 kcal), normal (ZN, 30 mg zinc per 4057 kcal) or supplement (ZS, 90 mg zinc per 4057 kcal). 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.

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