Adaptive versus maladaptive cardiac remodelling in response to sustained ß-adrenergic stimulation in a new 'ISO on/off model'.

On the one hand, sustained ß-adrenergic stress is a hallmark of heart failure (HF) and exerts maladaptive cardiac remodelling. On the other hand, acute ß-adrenergic stimulation maintains cardiac function under physiological stress. However, it is still incompletely understood to what extent the adaptive component of ß-adrenergic signaling contributes to the maintenance of cardiac function during chronic ß-adrenergic stress. We developed an experimental catecholamine-based protocol to distinguish adaptive from maladaptive effects. Mice were for 28 days infused with 30 mg/kg body weight/day isoproterenol (ISO) by subcutaneously implanted osmotic minipumps ('ISO on'). In a second and third group, ISO infusion was stopped after 26 days and the mice were observed for additional two or seven days without further ISO infusion ('ISO off short', 'ISO off long'). In this setup, 'ISO on' led to cardiac hypertrophy and slightly improved cardiac contractility. In stark contrast, 'ISO off' mice displayed progressive worsening of left ventricular ejection fraction that dropped down below 40%. While fetal and pathological gene expression (increase in Nppa, decrease in Myh6/Myh7 ratios, increase in Xirp2) was not induced in 'ISO on', it was activated in 'ISO off' mice. After ISO withdrawal, phosphorylation of phospholamban (PLN) at the protein kinase A (PKA) phosphorylation site Ser-16 dropped down to 20% as compared to only 50% at the Ca2+/Calmodulin-dependent kinase II (CaMKII) phosphorylation site Thr-17 in 'ISO off' mice. PKA-dependent cardioprotective production of the N-terminal proteolytic product of histone deacetylase 4 (HDAC4-NT) was reduced in 'ISO off' as compared to 'ISO on'. Taken together, these data indicate that chronic ISO infusion induces besides maladaptive remodelling also adaptive PKA signalling to maintain cardiac function. The use of the 'ISO on/off' model will further enable the separation of the underlying adaptive from maladaptive components of ß-adrenergic signalling and may help to better define and test therapeutic targets downstream of ß-adrenergic receptors.

Learned helplessness reveals a population at risk for depressive-like behaviour after myocardial infarction in mice.

AIMS: Myocardial infarction (MI) and heart failure (HF) are risk factors for the development of depression, additionally worsening the quality of life and patient outcome. How HF causes depression and how depression promotes HF remain mechanistically unclear, which is at least partly caused by the difficulty of in vivo modelling of psychosomatic co-morbidity. We aimed to study the potential sequence of events with respect to different depression aspects upon HF. METHODS AND RESULTS: Male C57BL6 mice underwent MI, followed by behavioural and echocardiographic characterization. Motility, exploration, and anxiety-like behaviour were unaffected in mice after MI. We did not observe increased depressive-like behaviour in the sucrose preference, tail suspension, or Porsolt forced swim test. Mice did not display signs of learned helplessness (LH) when compared to sham. Accordingly, cluster analysis revealed only a slightly higher quota of LH in HF (38%) vs. sham mice (32%). But strikingly, three-group cluster analysis revealed an additional intermediate subpopulation at risk for LH after HF (29%). Interestingly, this population featured elevated cardiac expression of nr4a1. CONCLUSIONS: The LH paradigm uncovered a subtle predisposition to depressive-like behaviour after MI, whereas testing for anhedonia and despair was insufficient to show a behavioural shift in mice. Therefore, we suggest an accumulating risk profile and a multiple-hits hypothesis regarding the pathogenesis of co-morbid depression after MI. Symptoms of LH may present a marker of subclinical depression after MI, the impact of which remains to be investigated. The proposed sequence of behavioural testing enables the mechanistic dissection of cardio-psychogenic signalling in the future.

CaM Kinase II mediates maladaptive post-infarct remodeling and pro-inflammatory chemoattractant signaling but not acute myocardial ischemia/reperfusion injury.

CaMKII was suggested to mediate ischemic myocardial injury and adverse cardiac remodeling. Here, we investigated the roles of different CaMKII isoforms and splice variants in ischemia/reperfusion (I/R) injury by the use of new genetic CaMKII mouse models. Although CaMKIIδC was upregulated 1 day after I/R injury, cardiac damage 1 day after I/R was neither affected in CaMKIIδ-deficient mice, CaMKIIδ-deficient mice in which the splice variants CaMKIIδB and C were re-expressed, nor in cardiomyocyte-specific CaMKIIδ/γ double knockout mice (DKO). In contrast, 5 weeks after I/R, DKO mice were protected against extensive scar formation and cardiac dysfunction, which was associated with reduced leukocyte infiltration and attenuated expression of members of the chemokine (C-C motif) ligand family, in particular CCL3 (macrophage inflammatory protein-1α, MIP-1α). Intriguingly, CaMKII was sufficient and required to induce CCL3 expression in isolated cardiomyocytes, indicating a cardiomyocyte autonomous effect. We propose that CaMKII-dependent chemoattractant signaling explains the effects on post-I/R remodeling. Taken together, we demonstrate that CaMKII is not critically involved in acute I/R-induced damage but in the process of post-infarct remodeling and inflammatory processes.