Ca+2/calmodulin-dependent protein kinase mediates glucose toxicity-induced cardiomyocyte contractile dysfunction

Area of Science:

• Cardiovascular Biology
• Cellular Physiology
• Biochemistry

Background:

• Hyperglycemia is known to induce cardiac cytotoxicity, leading to cardiomyocyte dysfunction.
• The precise mechanisms underlying glucose toxicity in the heart remain incompletely understood.
• Extracellular calcium's role in modulating glucose toxicity effects on cardiac function is an area requiring further investigation.

Purpose of the Study:

• To investigate the impact of elevated extracellular calcium on high glucose-induced cardiac contractile and intracellular calcium anomalies.
• To elucidate the underlying mechanisms, with a specific focus on the involvement of Ca(2+)/calmodulin (CaM)-dependent kinase.

Main Methods:

• Isolated adult rat cardiomyocytes were cultured in normal or high glucose media.
• Cardiac mechanical function was assessed using indices like peak shortening and maximal velocity of shortening/relengthening.
• Intracellular calcium handling and the expression/activity of key regulatory proteins were analyzed.
• The effects of varying extracellular calcium concentrations and a CaM kinase inhibitor (KN93) were evaluated.

Main Results:

• High glucose exposure resulted in impaired cardiomyocyte mechanical function and altered intracellular calcium handling.
• SERCA activity was inhibited by high glucose, despite unaffected expression of key regulatory proteins.
• Elevated extracellular calcium (2.7 mM) significantly ameliorated the high glucose-induced mechanical defects.
• The protective effect of high extracellular calcium was abolished by the CaM kinase inhibitor KN93.

Conclusions:

• Elevated extracellular calcium exhibits a protective effect against high glucose-induced cardiomyocyte contractile dysfunction.
• This protective mechanism appears to be mediated through the activation of Ca(2+)/calmodulin (CaM)-dependent kinase.
• These findings offer insights into potential therapeutic strategies for managing hyperglycemia-related cardiac complications.