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Metallothionein alleviates cardiac dysfunction in streptozotocin-induced diabetes: role of Ca2+ cycling proteins, NADPH oxidase, poly(ADP-Ribose) polymerase and myosin heavy chain isozyme.
Free Radic Biol Med. 2006 Apr 15; 40(8):1419-29.FR

Abstract

Diabetic cardiomyopathy contributes to high morbidity and mortality in diabetic populations. It is manifested by compromised ventricular contraction and prolonged relaxation attributable to multiple causative factors including oxidative stress. This study was designed to examine the effect of cardiac overexpression of the heavy metal scavenger metallothionein (MT) on cardiac contractile function, intracellular Ca(2+) cycling proteins, stress-activated signaling molecules and the myosin heavy chain (MHC) isozyme in diabetes. Adult male wild-type (FVB) and MT transgenic mice were made diabetic by a single injection of streptozotocin (STZ). Contractile properties were evaluated in cardiomyocytes including peak shortening (PS), time-to-PS (TPS), time-to-relengthening (TR(90)), maximal velocity of shortening/relengthening (+/-dL/dt) and intracellular Ca(2+) fluorescence. Diabetes significantly depressed PS, +/-dL/dt, prolonged TPS, TR(90) and intracellular Ca(2+) clearing, elevated resting intracellular Ca(2+), reduced caffeine-induced sarcoplasmic reticulum Ca(2+) release and dampened stress tolerance at high stimulus frequencies. MT itself exhibited little effect on myocyte mechanics but it significantly alleviated STZ-induced myocyte contractile dysfunctions. Diabetes enhanced expression of the AT(1) receptor, phospholamban, the p47(phox) NADPH oxidase subunit and poly(ADP-ribose) polymerase (PARP), depressed the level of SERCA2a, Na(+)-Ca(2+) exchanger and triggered a beta-MHC isozyme switch. All of these STZ-induced alterations with the exception of depressed SERCA2a and enhanced phospholamban were reconciled by MT. Collectively, these data suggest a beneficial effect of MT in the therapeutics of diabetic cardiomyopathy, possibly through a mechanism related to NADPH oxidase, PARP and MHC isozyme switch.

Authors+Show Affiliations

Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine, Grand Forks, 58203, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo 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

16631532

Citation

Wold, Loren E., et al. "Metallothionein Alleviates Cardiac Dysfunction in Streptozotocin-induced Diabetes: Role of Ca2+ Cycling Proteins, NADPH Oxidase, poly(ADP-Ribose) Polymerase and Myosin Heavy Chain Isozyme." Free Radical Biology & Medicine, vol. 40, no. 8, 2006, pp. 1419-29.
Wold LE, Ceylan-Isik AF, Fang CX, et al. Metallothionein alleviates cardiac dysfunction in streptozotocin-induced diabetes: role of Ca2+ cycling proteins, NADPH oxidase, poly(ADP-Ribose) polymerase and myosin heavy chain isozyme. Free Radic Biol Med. 2006;40(8):1419-29.
Wold, L. E., Ceylan-Isik, A. F., Fang, C. X., Yang, X., Li, S. Y., Sreejayan, N., Privratsky, J. R., & Ren, J. (2006). Metallothionein alleviates cardiac dysfunction in streptozotocin-induced diabetes: role of Ca2+ cycling proteins, NADPH oxidase, poly(ADP-Ribose) polymerase and myosin heavy chain isozyme. Free Radical Biology & Medicine, 40(8), 1419-29.
Wold LE, et al. Metallothionein Alleviates Cardiac Dysfunction in Streptozotocin-induced Diabetes: Role of Ca2+ Cycling Proteins, NADPH Oxidase, poly(ADP-Ribose) Polymerase and Myosin Heavy Chain Isozyme. Free Radic Biol Med. 2006 Apr 15;40(8):1419-29. PubMed PMID: 16631532.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Metallothionein alleviates cardiac dysfunction in streptozotocin-induced diabetes: role of Ca2+ cycling proteins, NADPH oxidase, poly(ADP-Ribose) polymerase and myosin heavy chain isozyme. AU - Wold,Loren E, AU - Ceylan-Isik,Asli F, AU - Fang,Cindy X, AU - Yang,Xiaoping, AU - Li,Shi-Yan, AU - Sreejayan,Nair, AU - Privratsky,Jamie R, AU - Ren,Jun, Y1 - 2006/01/06/ PY - 2005/10/07/received PY - 2005/11/16/revised PY - 2005/12/12/accepted PY - 2006/4/25/pubmed PY - 2006/6/10/medline PY - 2006/4/25/entrez SP - 1419 EP - 29 JF - Free radical biology & medicine JO - Free Radic Biol Med VL - 40 IS - 8 N2 - Diabetic cardiomyopathy contributes to high morbidity and mortality in diabetic populations. It is manifested by compromised ventricular contraction and prolonged relaxation attributable to multiple causative factors including oxidative stress. This study was designed to examine the effect of cardiac overexpression of the heavy metal scavenger metallothionein (MT) on cardiac contractile function, intracellular Ca(2+) cycling proteins, stress-activated signaling molecules and the myosin heavy chain (MHC) isozyme in diabetes. Adult male wild-type (FVB) and MT transgenic mice were made diabetic by a single injection of streptozotocin (STZ). Contractile properties were evaluated in cardiomyocytes including peak shortening (PS), time-to-PS (TPS), time-to-relengthening (TR(90)), maximal velocity of shortening/relengthening (+/-dL/dt) and intracellular Ca(2+) fluorescence. Diabetes significantly depressed PS, +/-dL/dt, prolonged TPS, TR(90) and intracellular Ca(2+) clearing, elevated resting intracellular Ca(2+), reduced caffeine-induced sarcoplasmic reticulum Ca(2+) release and dampened stress tolerance at high stimulus frequencies. MT itself exhibited little effect on myocyte mechanics but it significantly alleviated STZ-induced myocyte contractile dysfunctions. Diabetes enhanced expression of the AT(1) receptor, phospholamban, the p47(phox) NADPH oxidase subunit and poly(ADP-ribose) polymerase (PARP), depressed the level of SERCA2a, Na(+)-Ca(2+) exchanger and triggered a beta-MHC isozyme switch. All of these STZ-induced alterations with the exception of depressed SERCA2a and enhanced phospholamban were reconciled by MT. Collectively, these data suggest a beneficial effect of MT in the therapeutics of diabetic cardiomyopathy, possibly through a mechanism related to NADPH oxidase, PARP and MHC isozyme switch. SN - 0891-5849 UR - https://www.unboundmedicine.com/medline/citation/16631532/Metallothionein_alleviates_cardiac_dysfunction_in_streptozotocin_induced_diabetes:_role_of_Ca2+_cycling_proteins_NADPH_oxidase_poly_ADP_Ribose__polymerase_and_myosin_heavy_chain_isozyme_ DB - PRIME DP - Unbound Medicine ER -