ACE-inhibition, but not weight reduction restores cardiomyocyte response to β-adrenergic stimulation in the metabolic syndrome

Abstract

BackgroundDiabetic cardiomyopathy is characterized by systolic and early diastolic ventricular dysfunction. In the metabolic syndrome (MS), ventricular stiffness is additionally increased in a later stage. It is unknown whether this is related to intrinsic cardiomyocyte dysfunction, extrinsic factors influencing cardiomyocyte contractility and/or cardiac function, or a combination of both. A first aim was to study cardiomyocyte contractility and Ca2+ handling in vitro in a mouse model of MS. A second aim was to investigate whether in vivo hypocaloric diet or ACE-inhibition (ACE-I) improved cardiomyocyte contractility in vitro, contractile reserve and Ca2+ handling.MethodsThis study was performed in LDL-receptor (LDLR−/−) and leptin-deficient (ob/ob), double knock-out mice (DKO), featuring obesity, type II diabetes, atherogenic dyslipidemia and hypertension. Single knock-out LDLR−/−, ob/ob and wild type mice were used as controls. Cellular contractility, Ca2+ handling and their response to in vivo treatment with diet or ACE-I were studied in isolated cardiomyocytes at baseline, during β-adrenergic stimulation or increased extracellular Ca2+, using field stimulation and patch-clamp.ResultsIn untreated conditions, prolongation of contraction-relaxation cycle and altered Ca2+ handling are observed in MS. Response to increased extracellular Ca2+ and β-adrenergic stimulation is impaired and could not be rescued by weight loss. ACE-I restored impaired response to β-adrenergic stimulation in MS, but not the decreased response to increased extracellular Ca2+.ConclusionsCardiomyocyte contractility and β-adrenergic response are impaired in MS, due to alterations in cellular Ca2+ handling. ACE-I, but not weight loss, is able to restore cardiomyocyte response to β-adrenergic stimulation in MS.

Onset of decreased heart work is correlated with increased heart rate and shortened QT interval in high-carbohydrate fed overweight rats

“…It seems that oxidation-induced disruption of cellular redistributed signaling molecules in response to insulin stimulation is associated with impaired insulin action in case of many pathological conditions such as obesity The clustering of metabolic abnormality is closely related to the progression of cardiovascular disorders (Balderas-Villalobos et al 2013;Merabet et al 2015;Okatan et al 2016). Indeed, a correlation between obesity, insulin resistance and contractile dyfunction at most due to defect in intracellular Ca 2+ handling in rat heart with MetS have been observed, previously (Balderas-Villalobos et al 2013;Nevelsteen et al 2013). ECG is one of the standard technologies used to monitor and assess cardiac function, and provide insight into the mechanisms driving myocardial pathology.…”

Functional and structural impact of pirfenidone on the alterations of cardiac disease and diabetes mellitus

“…With regard to Ca V 1.2, the studies report either no changes [21,25,26,41,50,58,59] or a significant reduction in the activity and/or expression [39,60]. The experimental models were myocytes from either S-IDRs or knock-out mice for leptin (ob/ob).…”

Investigating interactions between epicardial adipose tissue and cardiac myocytes: what can we learn from different approaches?

“…Animal tissue has also been cultured for this purpose by Greulich et al () (guinea pigs and rats), Chilukoti et al () (pigs and rats) and Lage et al () (neonatal rats and cell lines). The availability of a range of mouse knockout strains has also been exploited by Nevelsteen et al (), studying cardiac myocyte function and obesity, although not specifically EAT, and by Castro et al (). This group reported on a wide‐ranging project in which they studied the metabolomics by MS‐NMR and looked at circadian rhythms of brown and white adipose tissue.…”