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 Ca2+ on glucose toxicity-induced cardiac contractile and intracellular Ca2+ anomalies as well as the mechanism(s) involved with a focus on Ca2+/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 (TR90). (3) Cardiomyocytes maintained with HG displayed abnormal mechanical function including reduced PS, ±dL/dt, and prolonged TPS, TR90 and intracellular Ca2+ clearance. Expression of intracellular Ca2+ regulatory proteins including SERCA2a, phospholamban and Na+-Ca2+ exchanger were unaffected whereas SERCA activity was inhibited by HG. Interestingly, the HG-induced mechanical anomalies were abolished by elevated extracellular Ca2+ (from 1.0 to 2.7 mM). Interestingly, the high extracellular Ca2+-induced beneficial effect against HG was abolished by the CaM kinase inhibitor KN93. (4) These data suggest that elevated extracellular Ca2+ protects against glucose toxicity-induced cardiomyocyte contractile defects through a mechanism associated with CaM kinase.
Highlights
Hyperglycemia in individuals with diabetes mellitus usually compromises myocardial contractile function and energy metabolism independent of macro- and microvascular coronary anomalies [1,2,3,4]
This study was designed to examine the impact of elevated extracellular Ca2+ levels mimicking a higher cardiac energy supply on cardiomyocyte contractile function and intracellular Ca2+ handling in cardiomyocytes maintained in normal glucose (NG) or high glucose (HG) environment
To examine the potential mechanism(s) behind the high glucose-induced cardiomyocyte contractile abnormalities, the glycation inhibitor aminoguanidine (1 mM), or the translation inhibitor cycloheximide was coincubated with adult rat cardiomyocytes for 12 hours maintained in either normal or high glucose medium
Summary
Hyperglycemia in individuals with diabetes mellitus usually compromises myocardial contractile function and energy metabolism independent of macro- and microvascular coronary anomalies [1,2,3,4]. CaMKII promotes cell survival in response to various stresses [16, 17], making CaMKII an important point of intersection for different pathways involved in diseases. To this end, this study was designed to examine the impact of elevated extracellular Ca2+ levels mimicking a higher cardiac energy supply on cardiomyocyte contractile function and intracellular Ca2+ handling in cardiomyocytes maintained in normal glucose (NG) or high glucose (HG) environment. Levels and activity of the intracellular Ca2+ regulatory proteins including sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA), phospholamban, and Na+/Ca2+ exchanger were examined
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have