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Metallothionein prevents high-fat diet induced cardiac contractile dysfunction: role of peroxisome proliferator activated receptor gamma coactivator 1alpha and mitochondrial biogenesis.
Diabetes 2007; 56(9):2201-12D

Abstract

Obesity is associated with oxidative stress and mitochondrial and myocardial dysfunction, although interaction among which remains elusive. This study was designed to evaluate the impact of the free radical scavenger metallothionein on high-fat diet-induced myocardial, intracellular Ca(2+), and mitochondrial dysfunction. FVB and metallothionein transgenic mice were fed a high- or low-fat diet for 5 months to induce obesity. Echocardiography revealed decreased fractional shortening, increased end-systolic diameter, and cardiac hypertrophy in high-fat-fed FVB mice. Cardiomyocytes from high-fat-fed FVB mice displayed enhanced reactive oxygen species (ROS) production, contractile and intracellular Ca(2+) defects including depressed peak shortening and maximal velocity of shortening/relengthening, prolonged duration of relengthening, and reduced intracellular Ca(2+) rise and clearance. Transmission microscopy noted overt mitochondrial damage with reduced mitochondrial density. Western blot analysis revealed enhanced phosphorylation of nuclear factor Foxo3a without changes in Foxo3a, Foxo1a, pFoxo1a, silent information regulator (Sirt), and Akt and pAkt in hearts of high-fat diet-fed FVB mice. The peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha), a key regulator of mitochondrial biogenesis, was significantly depressed by high-fat diet feeding and in vitro palmitic acid treatment. RT-PCR further depicted reduced levels of the PGC-1alpha downstream nuclear respiratory factors 1 and 2, mitochondrial transcription factor A, and mitochondrial DNA copy number in hearts of high-fat-fed FVB mice. Intriguingly, the high-fat diet-induced alterations in ROS, myocardial contractile, and mitochondrial and cell signaling were negated by metallothionein, with the exception of pFoxo3a. These data suggest that metallothionein may protect against high-fat diet-induced cardiac dysfunction possibly associated with upregulation of PGC-1alpha and preservation of mitochondrial biogenesis.

Authors+Show Affiliations

Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, WY 82071, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17575086

Citation

Dong, Feng, et al. "Metallothionein Prevents High-fat Diet Induced Cardiac Contractile Dysfunction: Role of Peroxisome Proliferator Activated Receptor Gamma Coactivator 1alpha and Mitochondrial Biogenesis." Diabetes, vol. 56, no. 9, 2007, pp. 2201-12.
Dong F, Li Q, Sreejayan N, et al. Metallothionein prevents high-fat diet induced cardiac contractile dysfunction: role of peroxisome proliferator activated receptor gamma coactivator 1alpha and mitochondrial biogenesis. Diabetes. 2007;56(9):2201-12.
Dong, F., Li, Q., Sreejayan, N., Nunn, J. M., & Ren, J. (2007). Metallothionein prevents high-fat diet induced cardiac contractile dysfunction: role of peroxisome proliferator activated receptor gamma coactivator 1alpha and mitochondrial biogenesis. Diabetes, 56(9), pp. 2201-12.
Dong F, et al. Metallothionein Prevents High-fat Diet Induced Cardiac Contractile Dysfunction: Role of Peroxisome Proliferator Activated Receptor Gamma Coactivator 1alpha and Mitochondrial Biogenesis. Diabetes. 2007;56(9):2201-12. PubMed PMID: 17575086.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Metallothionein prevents high-fat diet induced cardiac contractile dysfunction: role of peroxisome proliferator activated receptor gamma coactivator 1alpha and mitochondrial biogenesis. AU - Dong,Feng, AU - Li,Qun, AU - Sreejayan,Nair, AU - Nunn,Jennifer M, AU - Ren,Jun, Y1 - 2007/06/15/ PY - 2007/6/19/pubmed PY - 2007/9/22/medline PY - 2007/6/19/entrez SP - 2201 EP - 12 JF - Diabetes JO - Diabetes VL - 56 IS - 9 N2 - Obesity is associated with oxidative stress and mitochondrial and myocardial dysfunction, although interaction among which remains elusive. This study was designed to evaluate the impact of the free radical scavenger metallothionein on high-fat diet-induced myocardial, intracellular Ca(2+), and mitochondrial dysfunction. FVB and metallothionein transgenic mice were fed a high- or low-fat diet for 5 months to induce obesity. Echocardiography revealed decreased fractional shortening, increased end-systolic diameter, and cardiac hypertrophy in high-fat-fed FVB mice. Cardiomyocytes from high-fat-fed FVB mice displayed enhanced reactive oxygen species (ROS) production, contractile and intracellular Ca(2+) defects including depressed peak shortening and maximal velocity of shortening/relengthening, prolonged duration of relengthening, and reduced intracellular Ca(2+) rise and clearance. Transmission microscopy noted overt mitochondrial damage with reduced mitochondrial density. Western blot analysis revealed enhanced phosphorylation of nuclear factor Foxo3a without changes in Foxo3a, Foxo1a, pFoxo1a, silent information regulator (Sirt), and Akt and pAkt in hearts of high-fat diet-fed FVB mice. The peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha), a key regulator of mitochondrial biogenesis, was significantly depressed by high-fat diet feeding and in vitro palmitic acid treatment. RT-PCR further depicted reduced levels of the PGC-1alpha downstream nuclear respiratory factors 1 and 2, mitochondrial transcription factor A, and mitochondrial DNA copy number in hearts of high-fat-fed FVB mice. Intriguingly, the high-fat diet-induced alterations in ROS, myocardial contractile, and mitochondrial and cell signaling were negated by metallothionein, with the exception of pFoxo3a. These data suggest that metallothionein may protect against high-fat diet-induced cardiac dysfunction possibly associated with upregulation of PGC-1alpha and preservation of mitochondrial biogenesis. SN - 1939-327X UR - https://www.unboundmedicine.com/medline/citation/17575086/Metallothionein_prevents_high_fat_diet_induced_cardiac_contractile_dysfunction:_role_of_peroxisome_proliferator_activated_receptor_gamma_coactivator_1alpha_and_mitochondrial_biogenesis_ L2 - http://diabetes.diabetesjournals.org/cgi/pmidlookup?view=long&pmid=17575086 DB - PRIME DP - Unbound Medicine ER -