BackgroundApelin, the endogenous ligand for the G protein-coupled apelin receptor, is an important regulator of the cardiovascular homoeostasis. We previously demonstrated that apelin is one of the most potent endogenous stimulators of cardiac contractility; however, its underlying signaling mechanisms remain largely elusive. In this study we characterized the contribution of protein kinase C (PKC), extracellular signal-regulated kinase 1/2 (ERK1/2) and myosin light chain kinase (MLCK) to the positive inotropic effect of apelin.Methods and ResultsIn isolated perfused rat hearts, apelin increased contractility in association with activation of prosurvival kinases PKC and ERK1/2. Apelin induced a transient increase in the translocation of PKCε, but not PKCα, from the cytosol to the particulate fraction, and a sustained increase in the phosphorylation of ERK1/2 in the left ventricle. Suppression of ERK1/2 activation diminished the apelin-induced increase in contractility. Although pharmacological inhibition of PKC attenuated the inotropic response to apelin, it had no effect on ERK1/2 phosphorylation. Moreover, the apelin-induced positive inotropic effect was significantly decreased by inhibition of MLCK, a kinase that increases myofilament Ca2+ sensitivity.ConclusionsApelin increases cardiac contractility through parallel and independent activation of PKCε and ERK1/2 signaling in the adult rat heart. Additionally MLCK activation represents a downstream mechanism in apelin signaling. Our data suggest that, in addition to their role in cytoprotection, modest activation of PKCε and ERK1/2 signaling improve contractile function, therefore these pathways represent attractive possible targets in the treatment of heart failure.

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Introduction Childhood maltreatment (CM) contributes to negative mental and physical health outcomes including major depressive disorder (MDD), and an elevated risk for cardiovascular disease (CDV) in adults. Also, childhood maltreatment can be related to mentalizing deficits in MDD. Cardio-metabolic diseases often coincide with MDD and worsen its course and outcome. Little is known on the interplay of these factors. Objectives We examined MDD patients with and without CM to explore the effects of CM on serum lipid and lipoprotein levels and assessed their mentalizing abilities. Self-oriented mentalizing was operationalized as emotional self-awareness/alexithymia, other-oriented mentalizing was defined as theory of mind (ToM). Methods MDD patients (N=42) and healthy controls (n=20) matched in age, sex, and lifestyle were investigated. Total cholesterol, triglycerides, high- and low-density lipoproteins (HDL-C and LDL-C), body mass index, and exercise in a typical week were measured. Beck Depression Inventory, Childhood Trauma Questionnaire, Toronto Alexithymia scale, and the Reading the mind in the Eyes Test were used to assess clinical symptoms, mentalizing abilities and CM. Results After controlling for depressive symptom severity, demographic and lifestyle variables, CM was found to be a strong predictor of serum lipid alterations. Mentalizing deficits correlated with CM. Serum triglycerides, HDL-C were significant predictors of ToM performance (P<0.05, and P=0.005) and alexithymia (P< 0.05, and P< 0.05) in the MDD group. Conclusions Several, inter-correlated pathways may mediate the undesirable effects of CM on the course and outcome of MDD. According to our preliminary results, diminished self-awareness and ToM can be possible mediating factors. Disclosure This work was financially supported by the Hungarian Brain Research Program (2017-1.2.1-NKP-2017-00002)

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