Abstract 15763: Modulation of CAMKII Expression by Estrogen Confers Cardioprotection in Isoproterenol-Induced Stress Cardiomyopathy in Mice
Background: Stress cardiomyopathy (SCM) is characterized by a transient contractile dysfunction of the left ventricle with a typical contraction pattern. Recently published data could show a sympathoadrenergic overstimulation in SCM. So far, the increased incidence of SCM in postmenopausal females remains unclear. Therefore, the aim of this study was to investigate the impact of estrogens in a mouse model of SCM.
Methods: For simulation of catecholamine overload, female wild-type mice (WT) and ovariectomized mice (OVX) received a single subcutaneous injection of isoproterenol (5 mg/kg BW). Healthy female mice served as control group. Functional parameters were investigated by echocardiography at baseline as well as 24 and 48 hours after isoproterenol injection. Morphological parameters were assessed by immunohistochemical staining of serial left-ventricular cross sections.
Results: Isoproterenol led to a contractile dysfunction in both study groups after 24 hours (EF WT: 50.94±2.16%, OVX: 50.52±1.32%, Control: 66.26±1.47%). The dysfunction was mainly due to a pronounced hypokinesia of the interventricular septum (IVS). WT mice revealed a normalization of the left ventricular function after 48 hours, while function was still affected in OVX (EF WT: 61.29±2.50% vs. OVX: 52.58±1.95%, p<0.05). Structural alterations could not be observed either in WT or in OVX. Molecularbiological analysis revealed an increased expression and protein amount of the calcium/calmodulin-dependent protein kinase II (CaMKII) in OVX compared to WT (p<0.05) with a maximum in the IVS (p<0.01). In addition, an increased apoptosis-rate could be observed in OVX mainly in the IVS. Furthermore, WT mice showed a strong activation of the cardioprotective PI3K/Akt-pathway detected by an increased phosphorylation of Akt (p<0.01). In OVX, no significant differences in the protein amount of phosphorylated Akt could be observed.
Conclusion: Excessive catecholamine stimulation causes a prolonged contractile dysfunction in estrogen-deficient mice. This is due to a significant upregulation of CaMKII, which leads to an increased number of apoptotic cells. Therefore, CaMKII represents a potential key target in the therapy of stress-induced cardiomyopathy.
- © 2011 by American Heart Association, Inc.