Adaptive versus maladaptive cardiac remodelling in response to sustained β-adrenergic stimulation in a new ‘ISO on/off model’

Abstract

On the one hand, sustained β-adrenergic stress is a hallmark of heart failure (HF) and exerts maladaptive cardiac remodelling. On the other hand, acute β-adrenergic stimulation maintains cardiac function under physiological stress. However, it is still incompletely understood to what extent the adaptive component of β-adrenergic signaling contributes to the maintenance of cardiac function during chronic β-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 β-adrenergic signalling and may help to better define and test therapeutic targets downstream of β-adrenergic receptors.

Chronic isoprenaline/phenylephrine vs. exclusive isoprenaline stimulation in mice: critical contribution of alpha1-adrenoceptors to early cardiac stress responses

“…However, cardiomyocyte-specific α 1A -AR overexpression was shown to drive progressive fibrosis and reactivation of genes encoding matricellular proteins in the absence of pharmacological or surgical interventions [ 6 ], and angiogenesis after myocardial infarction [ 80 ], indicating a potential role for α 1 -AR signaling in cell–cell communication and organ homeostasis. If the early increase in fibroblast response in this study will also manifest in a more severe cardiac fibrosis under long-term ISO/PE challenge or lack relevant fibrotic cardiac remodeling as often reported from the ISO model [ 15 , 17 , 74 ] has yet to be investigated. Under both ISO and ISO/PE treatment, activation of fibroblast associated genes ( Tgfb1, Postn, Col1a1 ) was no longer observed at 7 d of exposure, and thus might rather reflect the previously reported timely correlation between gene programs involved in fibroblast activity and hypertrophic growth than the onset of fibrosis [ 11 , 54 , 63 ].…”

AKAP12 Upregulation Associates With PDE8A to Accelerate Cardiac Dysfunction

“…In the WT groups, we noticed that the Ejection Fraction % (EF%) and Fractional Shortening % (FS%) showed divergent responses after 14 days of treatment with 60 mg/kg per day of ISO; where some mice exhibited an increase in EF% and FS% while others experienced a decrease, aligning with prior findings with variable ISO doses. 22–24 However, all male and female AKAP12 OX mice demonstrated reduced EF% and FS% after the 14-day treatment period (Figure 7A, 7B, 7E, and 7F).…”

“…In the WT groups, we noticed that the Ejection Fraction % (EF%) and Fractional Shortening % (FS%) showed divergent responses after 14 days of treatment with 60 mg/kg per day of ISO; where some mice exhibited an increase in EF% and FS% while others experienced a decrease, aligning with prior findings with variable ISO doses. [22][23][24] However, all male and female AKAP12 OX mice demonstrated reduced EF% and FS% after the 14-day treatment period (Figure 7A, 7B, 7E, and 7F). Precisely, both male and female AKAP12 OX mice had significantly lower EF% (42.97±5.78% and 43.89±3.61%) as compared with WT littermates post-ISO treatment (65.22±4.07% and 57.39±3.95%; P=9.9×10 −3 and P=3.5×10 −2 ), respectively.…”

MSK-Mediated Phosphorylation of Histone H3 Ser28 Couples MAPK Signalling with Early Gene Induction and Cardiac Hypertrophy

“…For these experiments, animals were infused for 15 min via the jugular vein with hypertrophic agonists. In particular, rats were infused with either subpressor levels of ET-1, previously shown to stimulate induction of hypertrophic gene expression, or with the synthetic β-adrenergic agonist isoproterenol (Iso), which is widely used under chronic conditions to evoke a pathological hypertrophic response and heart failure involving CM hypertrophy [ 5 , 52 , 53 ]. To selectively quantitate pH3S28 in CMs and not in other cardiac cell types, which are in the majority in the heart, pH3S28 was measured by confocal imaging of immunostained heart sections.…”