Tale of two kinases: Protein kinase A and Ca2+/calmodulin-dependent protein kinase II in pre-diabetic cardiomyopathy

Abstract

Metabolic syndrome is a pre-diabetic state characterized by several biochemical and physiological alterations, including insulin resistance, visceral fat accumulation, and dyslipidemias, which increase the risk for developing cardiovascular disease. Metabolic syndrome is associated with augmented sympathetic tone, which could account for the etiology of pre-diabetic cardiomyopathy. This review summarizes the current knowledge of the pathophysiological consequences of enhanced and sustained β-adrenergic response in pre-diabetes, focusing on cardiac dysfunction reported in diet-induced experimental models of pre-diabetic cardiomyopathy. The research reviewed indicates that both protein kinase A and Ca²⁺/calmodulin-dependent protein kinase II play important roles in functional responses mediated by β₁-adrenoceptors; therefore, alterations in the expression or function of these kinases can be deleterious. This review also outlines recent information on the role of protein kinase A and Ca²⁺/calmodulin-dependent protein kinase II in abnormal Ca²⁺ handling by cardiomyocytes from diet-induced models of pre-diabetic cardiomyopathy.

Keywords: Ca²⁺/calmodulin-dependent protein kinase II, Protein kinase A, Metabolic syndrome, Pre-diabetes, Pre-diabetic cardiomyopathy, β-Adrenoceptors

Core Tip: Metabolic syndrome affects heart function leading to pre-diabetic cardiomyopathy. In an attempt to overcome contractility dysfunction, the activity of the sympathetic nervous system increases, but chronic stimulation of β-adrenoceptors leads to alterations in both protein kinase A and Ca²⁺/calmodulin-dependent protein kinase II activity, the main effectors of the β-adrenergic response. This work recapitulates current evidence about the participation of protein kinase A and Ca²⁺/calmodulin-dependent protein kinase II in experimental pre-diabetic cardiomyopathy, emphasizing the prevailing role of CaMKII in the development of cardiomyocyte Ca²⁺ mishandling and myocardial dysfunction associated with pre-diabetes.