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

Abstract

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.

New Therapeutic Agents in Obesity-Related Cardiovascular Disorders: Molecular and Cellular Insights

“…There were also marked decrease in the basal cAMP level, increased protein expression levels of phosphodiesterases (i.e. PDE3, and PDE4) in those cardiomyocytes [80]. Interestingly, there was significantly shorten QT-interval (at least through a less cAMP-release) in the ECGs of 16-week MetS rats (mimicing an early syndrome), being correlated with a depressed cardiac output and an increased heart rate [81].…”

Understanding the Role of SERCA2a Microdomain Remodeling in Heart Failure Induced by Obesity and Type 2 Diabetes

“…Considering how alterations in PDE activity may dysregulate SERCA2a activity, it was reported recently that hyperinsulinemia induces systolic and diastolic dysfunction by increasing expression of PDE4D, which contributes to reduced PKA mediated phosphorylation of PLN [ 64 ]. Additionally, in response to a high-carbohydrate-diet-induced metabolic syndrome in rats, elevated PDE3 and PDE4 expression was associated with a decreased phosphorylation of PLN and altered calcium homeostasis [ 65 ]. However, a limitation of these studies was that assessments of PDEs were made at the whole cell lysate/tissue level.…”