Blockade of PI3Kγ may provide a dual therapeutic advantage in cancer therapy by simultaneously preventing anthracyclines cardiotoxicity and reducing tumor growth.

AP39 protects against reperfusion injury independently of the cytosolic RISK pathway. This cardioprotective effect could be mediated by inhibiting PTP via a cyclophilin D-independent mechanism. Thus, selective delivery of H S to mitochondria may be therapeutically applicable for employing the cardioprotective utility of H S.

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The transcriptional regulator JDP2 (Jun dimerization protein 2) has been identified as a prognostic marker for patients to develop heart failure after myocardial infarction. We now performed in vivo studies on JDP2-overexpressing mice, to clarify the impact of JDP2 on heart failure progression. Therefore, during birth up to the age of 4 weeks cardiac-specific JDP2 overexpression was prevented by doxycycline feeding in transgenic mice. Then, JDP2 overexpression was started. Already after 1 week, cardiac function, determined by echocardiography, decreased which was also resembled on the cardiomyocyte level. After 5 weeks blood pressure declined, ejection fraction and cardiac output was reduced and left ventricular dilatation developed. Heart weight/body weight, and mRNA expression of ANP, inflammatory marker genes, collagen and fibronectin increased. Collagen 1 protein expression increased, and fibrosis developed. As an additional sign of elevated extracellular matrix remodeling, matrix metalloproteinase 2 activity increased in JDP2 mice. Thus, JDP2 overexpression is deleterious to heart function in vivo. It can be concluded that JDP2 overexpression provokes cardiac dysfunction in adult mice that is accompanied by hypertrophy and fibrosis. Thus, induction of JDP2 is a maladaptive response contributing to heart failure development.

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The leading cause of death in pulmonary arterial hypertension (PAH) is right ventricular (RV) failure (RVF). Reactive oxygen species (ROS) have been suggested to play a role in the development of RV hypertrophy (RVH) and the transition to RVF. The hydrogen peroxide-generating protein p66shc has been associated with left ventricular (LV) hypertrophy but its role in RVH is unclear. The purpose of this study was to determine whether genetic deletion of p66shc affects the development and/or progression of RVH and RVF in the pulmonary artery banding (PAB) model of RV pressure overload. The impact of p66shc on mitochondrial ROS formation, RV cardiomyocyte function, as well as on RV morphology and function were studied three weeks after PAB or sham operation. PAB in wild type mice did not affect mitochondrial ROS production or RV cardiomyocyte function, but induced RVH and impaired cardiac function. Genetic deletion of p66shc did also not alter basal mitochondrial ROS production or RV cardiomyocyte function, but impaired RV cardiomyocyte shortening was observed following PAB. The development of RVH and RVF following PAB was not affected by p66shc deletion. Thus, our data suggest that p66shc-derived ROS are not involved in the development and progression of RVH or RVF in PAH.

Background: TGFβ1 is a growth factor that plays a major role in the remodeling process of the heart by inducing cardiomyocyte dysfunction and apoptosis, as well as fibrosis thereby restricting heart function. TGFβ1 mediates its effect via the TGFβ receptor I (ALK5) and the activation of SMAD transcription factors, but TGFβ1 is also known as activator of phosphoinositide-3-kinase (PI3K) via the non-SMAD signaling pathway. The aim of this study was to investigate whether PI3K is also involved in TGFβ1–induced cardiomyocytes apoptosis and contractile dysfunction. Methods and Results: Incubation of isolated ventricular cardiomyocytes with TGFβ1 resulted in impaired contractile function. Pre-incubation of cells with the PI3K inhibitor Ly294002 or the ALK5 inhibitor SB431542 attenuated the decreased cell shortening in TGFβ1–stimulated cells. Additionally, TGFβ-induced apoptosis was significantly reduced by the PI3K inhibitor Ly294002. Administration of a PI3Kγ-specific inhibitor AS605240 abolished the TGFβ effect on apoptosis and cell shortening. This was also confirmed in cardiomyocytes from PI3Kγ KO mice. Induction of SMAD binding activity and the TGFβ target gene collagen 1 could be blocked by the PI3K inhibitor Ly294002, but not by the specific PI3Kγ inhibitor AS605240. Conclusions: TGFβ1-induced SMAD activation, cardiomyocyte apoptosis, and impaired cell shortening are mediated via both, the ALK5 receptor and PI3K, in adult cardiomyocytes. PI3Kγ specifically contributes to apoptosis induction and impairment of contractile function independent of SMAD signaling.

Introduction JDP2 (Jun Dimerization Protein 2) was recently characterized as potential prognostic marker for progression of heart failure after myocardial infarction. Furthermore, persistent cardiac-specific JDP2 overexpression provokes ventricular dysfunction, atrial dilatation and atrial fibrillation. Purpose In this study we investigated, if ventricular dysfunction is predisposed to atrial fibrillation. Therefore, we analyzed ventricular function in mice with 1 and 5 weeks of JDP2 overexpression and compared gene expression in ventricular and atrial tissues at these time points. Methods JDP2 expression was under control of a Tet-off system. Therefore, JDP2 overexpression was started by withdrawal of doxycycline diet in 4-week-old mice. After 1 or 5 weeks, cardiac function was determined by echocardiography and ECG. mRNA expression was analyzed by real-time RT-PCR and protein expression in western blots. Results After 1 or 5 weeks, JDP2 mRNA levels were increased in ventricular and atrial tissues of JDP2 mice. Already after 1 week ventricular dysfunction emerged in JDP2 mice: Ejection fraction decreased from 64.6±10.4% in WT to 58.8±9.3% in JDP2 mice, fractional shortening from 38.3±7.9% in WT to 27.4±4.8% in JDP -mice, and cardiac output from 23.0±4.7 ml/min in WT to 19.4±3.3 ml/min in JDP2 mice (n=11–16, p<0.05). In ventricular tissues, elastin mRNA expression increased, and the calcium handling protein SERCA decreased within one week of JDP2 overexpression (n=6, p<0.05 vs. WT). After 5 weeks of JDP2 overexpression ventricular dysfunction became even stronger with a cardiac output of 13.6±2.5 ml/min (n=11, p<0.05 vs. WT). Still reduction in SERCA protein was observed, and increased mRNA levels of fibrotic marker genes were detected, as well as contractile function of isolated cardiomyocytes of JDP2 mice continued to decline. In atrial tissue, besides the 3.6 times increase of JDP2 mRNA, no changes could be detected within one week. In addition, ECG recordings over 30 minutes on awake mice did not show any abnormalities after one week of JDP2-overexpression. Atrial dilatation became evident only after 5 weeks of JDP2 overexpression. ECG-recordings revealed prolonged PR-intervals (34.6±3.9 ms in JDP2-mice vs. 30.2±7.0 ms in WT) and broadened QRS-complexes (15.8±2.8 ms in JDP2 mice vs. 13.9±1.7 ms in WT, n=10–12, p<0.05). At the same time point, mRNA of the calcium-handling proteins PLB, NCX and SERCA, and of the fibrotic marker genes collagen I, fibronectin and elastin were dramatically reduced in atrial tissue of JDP2 compared to WT mice (n=6, p<0.05), and may be functionally involved in atrial conduction defects. Conclusion Enhanced expression of JDP2 provokes ventricular dysfunction and fibrosis within one week, whereas changes in the atrial tissue and conduction defects occur later and seem to be a secondary effect that is provoked by the pre-existing ventricular dysfunction.