The contribution of phosphodiesterases to cardiac dysfunction in rats with metabolic syndrome induced by a high-carbohydrate diet

Metabolic syndrome (MetS) is a cluster of risk factors, including insulin resistance among others, underlying the development of diabetes and (or) cardiovascular diseases. Studies show a close relationship between cardiac dysfunction and abnormal cAMP catabolism, which contributes to pathological remodelling. Stimulating the synthesis of cAMP via suppression of phosphodiesterases (PDEs) has positive therapeutic effects. Therefore, we examined the role of PDEs on cardiac dysfunction in high-carbohydrate diet-induced MetS rats. We first demonstrated significantly high expression levels of PDE3 and PDE4, the most highly expressed subtypes, together with depressed cAMP levels in heart tissue from MetS rats. Second, we demonstrated the activity of these PDEs by using either their basal or PDE inhibitor-induced intracellular levels of cAMP and Ca²⁺, the transient intracellular Ca²⁺ changes under electrical stimulation, isometric contractions in papillary muscle strips and some key signalling proteins (such as RyR2, PLN, PP1A, and PKA) are responsible for the Ca²⁺ homeostasis in isolated cardiomyocytes from MetS rats. The clear recovery in decreased basal cAMP levels, increased protein expression levels of PDE3 and PDE4, and positive responses in the altered Ca²⁺ homeostasis to PDE inhibitors as seen in our study can provide important insights about the roles of activated PDEs in depressed contractile activity in hearts from MetS rats.