Intracellular calcium mishandling leads to cardiac dysfunction and ventricular arrhythmias in a mouse model of propionic acidemia.

Propionic acidemia (PA) is a rare metabolic disease associated with mutations in genes encoding the α and ß subunits of the enzyme propionyl-CoA carboxylase. The accumulation of toxic metabolites results in mitochondrial dysfunction, increased reactive oxygen species production and oxidative damage, which have been associated with the disease pathophysiology. Clinical symptoms are heterogeneous and include cardiac complications, mainly cardiac dysfunction and arrhythmias, which are recognized as one of the major life-threatening manifestations in patients. We aimed to investigate the molecular mechanisms underlying the cardiac phenotype using a hypomorphic mouse model (Pcca-/-(A138T)) that recapitulates some biochemical and clinical characteristics of PA. We demonstrate that Pcca-/-(A138T) mice present with depressed cardiac function along with impaired cell contractility when compared to the wild-type mice. Cardiac dysfunction in Pcca-/-(A138T) mice was associated with lower systolic Ca2+ release ([Ca2+]i transients), impairment in the sarcoplasmic reticulum (SR) Ca2+ load and decreased Ca2+ re-uptake by SR-Ca2+ ATPase (SERCA2a). These functional changes correlated well with the depressed activity of SERCA2a, the elevated ROS levels and SERCA2a oxidation rate in cardiomyocytes isolated from Pcca-/-(A138T) mice. In addition, decreased SR-Ca2+ load in Pcca-/-(A138T) cardiomyocytes was associated with increased diastolic Ca2+ release. The increase in Ca2+ sparks, Ca2+ waves and spontaneous [Ca2+]i transients in Pcca-/-(A138T) cardiomyocytes could be responsible for the induction of ventricular arrhythmias detected in these mice. Overall, our results uncover the role of impaired Ca2+ handling in arrhythmias and cardiac dysfunction in PA, and identify new targets for the development of therapeutic approaches for this devastating metabolic disease.

PGE2 induces apoptosis of hepatic stellate cells and attenuates liver fibrosis in mice by downregulating miR-23a-5p and miR-28a-5p.

MicroRNAs (miRNAs), small noncoding RNAs modulating messenger RNA (mRNA) and protein expression, have emerged as key regulatory molecules in chronic liver diseases, whose end stage is hepatic fibrosis, a major global health burden. Pharmacological strategies for prevention or treatment of hepatic fibrosis are still limited, what makes it necessary to establish a better understanding of the molecular mechanisms underlying its pathogenesis. In this context, we have recently shown that cyclooxygenase-2 (COX-2) expression in hepatocytes restricts activation of hepatic stellate cells (HSCs), a pivotal event in the initiation and progression of hepatic fibrosis. Here, we evaluated the role of COX-2 in the regulation of a specific set of miRNAs on a mouse model of CCl4 and bile duct ligation (BDL)-induced liver fibrosis. Our results provide evidence that COX-2 represses miR-23a-5p and miR-28-5p expression in HSC. The decrease of miR-23a-5p and miR-28-5p expression promotes protection against fibrosis by decreasing the levels of pro-fibrogenic markers α-SMA and COL1A1 and increasing apoptosis of HSC. Moreover, we demonstrate that serum levels of miR-28-5p are decreased in patients with chronic liver disease. These results suggest a protective effect exerted by COX-2-derived prostanoids in the process of hepatofibrogenesis.

Labdane diterpenes protect against anoxia/reperfusion injury in cardiomyocytes: involvement of AKT activation.

Several labdane diterpenes exert anti-inflammatory and cytoprotective actions; therefore, we have investigated whether these molecules protect cardiomyocytes in an anoxia/reperfusion (A/R) model, establishing the molecular mechanisms involved in the process. The cardioprotective activity of three diterpenes (T1, T2 and T3) was studied in the H9c2 cell line and in isolated rat cardiomyocyte subjected to A/R injury. In both cases, treatment with diterpenes T1 and T2 protected from A/R-induced apoptosis, as deduced by a decrease in the percentage of apoptotic and caspase-3 active positive cells, a decrease in the Bcl-2/Bax ratio and an increase in the expression of antiapoptotic proteins. Analysis of cell survival signaling pathways showed that diterpenes T1 and T2 added after A/R increased phospho-AKT and phospho-ERK 1/2 levels. These cardioprotective effects were lost when AKT activity was pharmacologically inhibited. Moreover, the labdane-induced cardioprotection involves activation of AMPK, suggesting a role for energy homeostasis in their mechanism of action. Labdane diterpenes (T1 and T2) also exerted cardioprotective effects against A/R-induced injury in isolated cardiomyocytes and the mechanisms involved activation of specific survival signals (PI3K/AKT pathways, ERK1/2 and AMPK) and inhibition of apoptosis.

Lipoxin A4 impairment of apoptotic signaling in macrophages: implication of the PI3K/Akt and the ERK/Nrf-2 defense pathways.

Lipoxin A(4) (LXA(4)) is an endogenous lipid mediator that requires transcellular metabolic traffic for its synthesis. The targets of LXA(4) on neutrophils are well described, contributing to attenuation of inflammation. However, effects of lipoxins on macrophage are less known, particularly the action of LXA(4) on the regulation of apoptosis of these cells. Our data show that pretreatment of human or murine macrophages with LXA(4) at the concentrations prevailing in the course of resolution of inflammation (nanomolar range) significantly inhibits the apoptosis induced by staurosporine, etoposide and S-nitrosoglutathione or by more pathophysiological stimuli, such as LPS/IFNgamma challenge. The release of mitochondrial mediators of apoptosis and the activation of caspases was abrogated in the presence of LXA(4). In addition to this, the synthesis of reactive oxygen species induced by staurosporine was attenuated and antiapoptotic proteins of the Bcl-2 family accumulated in the presence of lipoxin. Analysis of the targets of LXA(4) identified an early activation of the PI3K/Akt and ERK/Nrf-2 pathways, which was required for the observation of the antiapoptotic effects of LXA(4). These data suggest that the LXA(4), released after the recruitment of neutrophils to sites of inflammation, exerts a protective effect on macrophage viability that might contribute to a better resolution of inflammation.

[Psychopathological characteristics of female victims of intimate partner violence]. / Características psicopatológicas de mujeres víctimas de violencia de pareja.

Psychopathological characteristics of female victims of intimate partner violence. Intimate partner violence has caused much social alarm. Knowing the characteristics and problems of the female victims of this type of violence is necessary to be able to provide adequate psychological attention. This is the purpose of the present study. We studied a sample of 212 women who had been exposed to a situation of intimate partner violence, were remitted by diverse institutions of the Community of Madrid, and who were evaluated by the same procedure. The results contribute data about the social-demographic characteristics and the history of violence, which resemble those obtained in previous investigations. Regarding psychopathological variables, there was a lower incidence of posttraumatic stress and a higher incidence of depression. The presence of some concomitant variables was observed, especially problems of adaptation, low self-esteem, and dysfunctional posttraumatic cognitions.

Características psicopatológicas de mujeres víctimas de violencia de pareja / Psychopathological characteristics of female victims of intimate partner violence

La violencia de pareja provoca gran alarma social. Conocer las características y problemáticas de las mujeres víctimas de este tipo de violencia parece necesario para poder ofrecer una atención psicológica adecuada. Éste es el objetivo del presente estudio. Se estudia una muestra de 212 mujeres que ha sufrido maltrato por su pareja, derivadas por diversas instituciones de la Comunidad de Madrid y que han sido evaluadas por el mismo procedimiento. Los resultados aportan datos sobre las características sociodemográficas y la historia de violencia que se asemejan a los obtenidos por investigaciones previas. En cuanto a las variables psicopatológicas aparece una menor incidencia del trastorno de estrés postraumático y mayor de depresión. Se observa la presencia de determinadas variables concomitantes, destacando problemas de adaptación, baja autoestima y cogniciones disfuncionales de tipo postraumático (AU)

Intimate partner violence has caused much social alarm. Knowing the characteristics and problems of the female victims of this type of violence is necessary to be able to provide adequate psychological attention. This is the purpose of the present study. We studied a sample of 212 women who had been exposed to a situation of intimate partner violence, were remitted by diverse institutions of the Community of Madrid, and who were evaluated by the same procedure. The results contribute data about the social-demographic characteristics and the history of violence, which resemble those obtained in previous investigations. Regarding psychopathological variables, there was a lower incidence of posttraumatic stress and a higher incidence of depression. The presence of some concomitant variables was observed, especially problems of adaptation, low self-esteem, and dysfunctional posttraumatic cognitions (AU)

Neuropeptide Y increases 4-aminopyridine-sensitive transient outward potassium current in rat ventricular myocytes.

1. The modulation of 4-aminopyridine sensitive transient outward potassium current (4-AP I(to)) by neuropeptide Y (NPY) (100 nM) in rat ventricular myocytes was examined using the whole cell voltage-clamp technique. 2. Continuous exposure to NPY (100 nM) for 3 - 6 h significantly increased 4-AP I(to) density. The stimulation of 4-AP I(to) density by NPY was concentration-dependent (EC(50)=10 nM). 3. In the presence of BIBP 3226, an NPY receptor antagonist that binds selectively to NPY Y1-receptors, the effect of NPY on 4-AP I(to) density was maintained. However, in the presence of BIIE 0246, a highly selective non-peptide NPY Y2-receptor antagonist, NPY was unable to increase 4-AP I(to) density. 4. The effect of NPY on 4-AP I(to) density was prevented by pretreatment with 500 ng ml(-1) pertussis toxin (PTX) and by the specific protein kinase C (PKC) inhibitor, calphostin C (100 nM). 5. Thus, short term exposure to NPY induces an increase of 4-AP I(to) density in rat ventricular myocytes mediated by Y2-receptors and involving the action of PKC via a PTX-sensitive signalling cascade.