title: Zinc deficiency exacerbates while zinc supplement attenuates cardiac hypertrophy in high-fat diet-induced obese mice through modulating p38 MAPK-dependent signaling.
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.
authors.affiliation: Cardiovascular Center, the First Hospital of Jilin University, Changchun, China; Department of Pediatrics, University of Louisville, Louisville, KY, USA.
authors.forename: Shudong
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, University of Louisville, Louisville, KY, USA; Department of Nephrology, the Second Hospital of Jilin University, Changchun, China.
authors.forename: Manyu
authors.initials: M
authors.lastname: Luo
authors.affiliation: Cardiovascular Center, the First Hospital of Jilin University, Changchun, China; Department of Pediatrics, University of Louisville, Louisville, KY, USA.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, University of Louisville, Louisville, KY, USA.
authors.forename: Junlian
authors.initials: J
authors.lastname: Gu
authors.affiliation: Department of Pediatrics, University of Louisville, Louisville, KY, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Pediatrics, University of Louisville, Louisville, KY, USA; Department of Internal Medicine, Marshall University Joan C. Edwards School of Medicine, Huntington, WV, USA.
authors.forename: Kristen McClung
authors.initials: KM
authors.lastname: Payne
authors.affiliation: Department of Pediatrics, University of Louisville, Louisville, KY, USA; Wendy Novak Diabetes Care Center, University of Louisville, Louisville, KY, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Tan
authors.affiliation: Cardiovascular Center, the First Hospital of Jilin University, Changchun, China.
authors.forename: Yuehui
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Cardiovascular Center, the First Hospital of Jilin University, Changchun, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Yin
authors.affiliation: Department of Chemistry, University of Louisville, Louisville, KY, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, University of Louisville, Louisville, KY, USA.
authors.forename: Gilbert C
authors.initials: GC
authors.lastname: Liu
authors.affiliation: Department of Pediatrics, University of Louisville, Louisville, KY, USA; Wendy Novak Diabetes Care Center, University of Louisville, Louisville, KY, USA.
authors.forename: Kupper
authors.initials: K
authors.lastname: Wintergerst
authors.affiliation: Cardiovascular Center, the First Hospital of Jilin University, Changchun, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Cardiovascular Center, the First Hospital of Jilin University, Changchun, China. Electronic address: zhengyang@jlu.edu.cn.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: 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.
authors.forename: Lu
authors.initials: L
authors.lastname: Cai
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D002478:Cells, Cultured; D002614:Chelating Agents / Q000009:adverse effects; D003677:Deficiency Diseases / Q000150:complications / Q000178:diet therapy* / Q000276:immunology; D059305:Diet, High-Fat / Q000009:adverse effects; D019587:Dietary Supplements; D004789:Enzyme Activation / Q000187:drug effects; D005230:Fatty Acids, Nonesterified / Q000009:adverse effects; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D009765:Obesity / Q000150:complications / Q000209:etiology / Q000276:immunology / Q000503:physiopathology*; D019308:Palmitic Acid / Q000009:adverse effects; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D034622:RNA Interference; D012720:Severity of Illness Index; D015032:Zinc / Q000737:chemistry / Q000172:deficiency* / Q000627:therapeutic use; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D002614:Chelating Agents; D005230:Fatty Acids, Nonesterified; D047428:Protein Kinase Inhibitors; D019308:Palmitic Acid; D048051:p38 Mitogen-Activated Protein Kinases; D015032:Zinc
keywords: Cardiac hypertrophy; Obesity; P38 MAPK; Zinc supplement