title: Ca+2/calmodulin-dependent protein kinase mediates glucose toxicity-induced cardiomyocyte contractile dysfunction.
abstract: (1) Hyperglycemia leads to cytotoxicity in the heart. Although several theories are postulated for glucose toxicity-induced cardiomyocyte dysfunction, the precise mechanism still remains unclear. (2) This study was designed to evaluate the impact of elevated extracellular Ca(2+) on glucose toxicity-induced cardiac contractile and intracellular Ca(2+) anomalies as well as the mechanism(s) involved with a focus on Ca(2+)/calmodulin (CaM)-dependent kinase. Isolated adult rat cardiomyocytes were maintained in normal (NG, 5.5 mM) or high glucose (HG, 25.5 mM) media for 6-12 hours. Contractile indices were measured including peak shortening (PS), maximal velocity of shortening/relengthening (±dL/dt), time-to-PS (TPS), and time-to-90% relengthening (TR(90)). (3) Cardiomyocytes maintained with HG displayed abnormal mechanical function including reduced PS, ±dL/dt, and prolonged TPS, TR(90) and intracellular Ca(2+) clearance. Expression of intracellular Ca(2+) regulatory proteins including SERCA2a, phospholamban and Na(+)-Ca(2+) exchanger were unaffected whereas SERCA activity was inhibited by HG. Interestingly, the HG-induced mechanical anomalies were abolished by elevated extracellular Ca(2+) (from 1.0 to 2.7 mM). Interestingly, the high extracellular Ca(2+)-induced beneficial effect against HG was abolished by the CaM kinase inhibitor KN93. (4) These data suggest that elevated extracellular Ca(2+) protects against glucose toxicity-induced cardiomyocyte contractile defects through a mechanism associated with CaM kinase.
authors: Department of Geriatrics, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors: Rong-Huai
authors: RH
authors: Zhang
authors: Haitao
authors: H
authors: Guo
authors: Machender R
authors: MR
authors: Kandadi
authors: Xiao-Ming
authors: XM
authors: Wang
authors: Jun
authors: J
authors: Ren
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1 / Q000378:metabolism*; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology / Q000633:toxicity*; D006943:Hyperglycemia; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000166:cytology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013314:Stress, Mechanical; D013997:Time Factors
chemical_list: D016895:Culture Media, Serum-Free; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1; D005947:Glucose; D002118:Calcium