Cardioprotective Effect of Resveratrol in a Postinfarction Heart Failure Model

Despite great advances in therapies observed during the last decades, heart failure (HF) remained a major health problem in western countries. In order to further improve symptoms and survival in patients with heart failure, novel therapeutic strategies are needed. In some animal models of HF resveratrol (RES), it was able to prevent cardiac hypertrophy, contractile dysfunction, and remodeling. Several molecular mechanisms are thought to be involved in its protective effects, such as inhibition of prohypertrophic signaling molecules, improvement of myocardial Ca2+ handling, regulation of autophagy, and the reduction of oxidative stress and inflammation. In our present study, we wished to further examine the effects of RES on prosurvival (Akt-1, GSK-3β) and stress signaling (p38-MAPK, ERK 1/2, and MKP-1) pathways, on oxidative stress (iNOS, COX-2 activity, and ROS formation), and ultimately on left ventricular function, hypertrophy and fibrosis in a murine, and isoproterenol- (ISO-) induced postinfarction heart failure model. RES treatment improved left ventricle function, decreased interstitial fibrosis, cardiac hypertrophy, and the level of plasma BNP induced by ISO treatment. ISO also increased the activation of P38-MAPK, ERK1/2Thr183-Tyr185, COX-2, iNOS, and ROS formation and decreased the phosphorylation of Akt-1, GSK-3β, and MKP-1, which were favorably influenced by RES. According to our results, regulation of these pathways may also contribute to the beneficial effects of RES in HF

Lack of cyclophilin D protects against the development of acute lung injury in endotoxemia.

Sepsis caused by LPS is characterized by an intense systemic inflammatory response affecting the lungs, causing acute lung injury (ALI). Dysfunction of mitochondria and the role of reactive oxygen (ROS) and nitrogen species produced by mitochondria have already been proposed in the pathogenesis of sepsis; however, the exact molecular mechanism is poorly understood. Oxidative stress induces cyclophilin D (CypD)-dependent mitochondrial permeability transition (mPT), leading to organ failure in sepsis. In previous studies mPT was inhibited by cyclosporine A which, beside CypD, inhibits cyclophilin A, B, C and calcineurin, regulating cell death and inflammatory pathways. The immunomodulatory side effects of cyclosporine A make it unfavorable in inflammatory model systems. To avoid these uncertainties in the molecular mechanism, we studied endotoxemia-induced ALI in CypD-/- mice providing unambiguous data for the pathological role of CypD-dependent mPT in ALI. Our key finding is that the loss of this essential protein improves survival rate and it can intensely ameliorate endotoxin-induced lung injury through attenuated proinflammatory cytokine release, down-regulation of redox sensitive cellular pathways such as MAPKs, Akt, and NF-kappaB and reducing the production of ROS. Functional inhibition of NF-kappaB was confirmed by decreased expression of NF-kappaB-mediated proinflammatory genes. We demonstrated that impaired mPT due to the lack of CypD reduces the severity of endotoxemia-induced lung injury suggesting that CypD specific inhibitors might have a great therapeutic potential in sepsis-induced organ failure. Our data highlight a previously unknown regulatory function of mitochondria during inflammatory response

Design and application of a novel ir emission liquid cell

A new IR emission liquid cell is designed to be suitable for measurements in liquid systems, including chemical reactions in liquid phase. The main advantage of the new cell is the variable sample layer thickness and a possibility to control reactions by dilatometry. The cell is equipped with a thermostate. Examples are shown to demonstrate how the cell can be used in IRES measurements in solvents and in liquid phase chemical reactions

BGP-15 Protects against Heart Failure by Enhanced Mitochondrial Biogenesis and Decreased Fibrotic Remodelling in Spontaneously Hypertensive Rats

Heart failure (HF) is a complex clinical syndrome with poor clinical outcomes despite the growing number of therapeutic approaches. It is characterized by interstitial fibrosis, cardiomyocyte hypertrophy, activation of various intracellular signalling pathways, and damage of the mitochondrial network. Mitochondria are responsible for supplying the energy demand of cardiomyocytes; therefore, the damage of the mitochondrial network causes cellular dysfunction and finally leads to cell death. BGP-15, a hydroxylamine derivative, is an insulin-sensitizer molecule and has a wide range of cytoprotective effects in animal as well as in human studies. Our recent work was aimed at examining the effects of BGP-15 in a chronic hypertension-induced heart failure model. 15-month-old male SHRs were used in our experiment. The SHR-Baseline group represented the starting point (n=7). Animals received BGP-15 (SHR-B, n=7) or placebo (SHR-C, n=7) for 18 weeks. WKY rats were used as age-matched normotensive controls (n=7). The heart function was monitored by echocardiography. Histological preparations were made from cardiac tissue. The levels of signalling proteins were determined by Western blot. At the end of the study, systolic and diastolic cardiac function was preserved in the BGP-treated animals. BGP-15 decreased the interstitial collagen deposition via decreasing the activity of TGFβ/Smad signalling factors and prevented the cardiomyocyte hypertrophy in hypertensive animals. BGP-15 enhanced the prosurvival signalling pathways (Akt/Gsk3β). The treatment increased the activity of MKP1 and decreased the activity of p38 and JNK signalling routes. The mitochondrial mass of cardiomyocytes was also increased in BGP-15-treated SHR animals due to the activation of mitochondrial biogenesis. The mitigation of remodelling processes and the preserved systolic cardiac function in hypertension-induced heart failure can be a result—at least partly—of the enhanced mitochondrial biogenesis caused by BGP-15

Doxycycline protects against ROS-induced mitochondrial fragmentation and ISO-induced heart failure.

In addition to their anti-bacterial action, tetracyclines also have complex biological effects, including the modification of mitochondrial protein synthesis, metabolism and gene-expression. Long-term clinical studies have been performed using tetracyclines, without significant side effects. Previous studies demonstrated that doxycycline (DOX), a major tetracyclin antibiotic, exerted a protective effect in animal models of heart failure; however, its exact molecular mechanism is still unknown. Here, we provide the first evidence that DOX reduces oxidative stress-induced mitochondrial fragmentation and depolarization in H9c2 cardiomyocytes and beneficially alters the expression of Mfn-2, OPA-1 and Drp-1 -the main regulators of mitochondrial fusion and fission-in our isoproterenol (ISO)-induced heart failure model, ultimately decreasing the severity of heart failure. In mitochondria, oxidative stress causes a shift toward fission which leads to mitochondrial fragmentation and cell death. Protecting mitochondria from oxidative stress, and the regulation of mitochondrial dynamics by drugs that shift the balance toward fusion, could be a novel therapeutic approach for heart failure. On the basis of our findings, we raise the possibility that DOX could be a novel therapeutic agent in the future treatment of heart failure

Chronic PARP-1 inhibition reduces carotid vessel remodeling and oxidative damage of the dorsal hippocampus in spontaneously hypertensive rats.

Vascular remodeling during chronic hypertension may impair the supply of tissues with oxygen, glucose and other compounds, potentially unleashing deleterious effects. In this study, we used Spontaneously Hypertensive Rats and normotensive Wistar-Kyoto rats with or without pharmacological inhibition of poly(ADP-ribose)polymerase-1 by an experimental compound L-2286, to evaluate carotid artery remodeling and consequent damage of neuronal tissue during hypertension. We observed elevated oxidative stress and profound thickening of the vascular wall with fibrotic tissue accumulation induced by elevated blood pressure. 32 weeks of L-2286 treatment attenuated these processes by modulating mitogen activated protein kinase phosphatase-1 cellular levels in carotid arteries. In hypertensive animals, vascular inflammation and endothelial dysfunction was observed by NF-κB nuclear accumulation and impaired vasodilation to acetylcholine, respectively. Pharmacological poly(ADP-ribose)polymerase-1 inhibition interfered in these processes and mitigated Apoptosis Inducing Factor dependent cell death events, thus improved structural and functional alterations of carotid arteries, without affecting blood pressure. Chronic poly(ADP-ribose)polymerase-1 inhibition protected neuronal tissue against oxidative damage, assessed by nitrotyrosine, 4-hydroxinonenal and 8-oxoguanosine immunohistochemistry in the area of Cornu ammonis 1 of the dorsal hippocampus in hypertensive rats. In this area, extensive pyramidal cell loss was also attenuated by treatment with lowered poly(ADP-ribose)polymer formation. It also preserved the structure of fissural arteries and attenuated perivascular white matter lesions and reactive astrogliosis in hypertensive rats. These data support the premise in which chronic poly(ADP-ribose)polymerase-1 inhibition has beneficial effects on hypertension related tissue damage both in vascular tissue and in the hippocampus by altering signaling events, reducing oxidative/nitrosative stress and inflammatory status, without lowering blood pressure

Resveratrol Improves Heart Function by Moderating Inflammatory Processes in Patients with Systolic Heart Failure

The effects of resveratrol (RES) in heart failure have already been evaluated in animal models; however, in human clinical trials, they have not been confirmed yet. The aim of this study was to assess the effects of resveratrol treatment in systolic heart failure patients (heart failure with reduced ejection fraction or HFrEF). In this human clinical trial, 60 outpatients with NYHA (New York Heart Association) class II-III HFrEF were enrolled and randomized into two groups: receiving either 100-mg resveratrol daily or placebo for three months. At the beginning and at the end of the study echocardiography, a six-minute walk test, spirometry, quality of life questionnaire, lab test and RNA profile analysis were performed. The systolic and diastolic left ventricular function, as well as the global longitudinal strain, were improved significantly in the resveratrol-treated group (RES). Exercise capacity, ventilation parameters and quality of life also improved significantly in the RES group. In parallel, the cardiac biomarker levels (N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and galectin-3) decreased in the treated group. The level of inflammatory cytokines decreased significantly after RES supplementation, as a consequence of the decreased expression level of leucocyte electron transport chain proteins. The main findings of our trial are that RES treatment added to the standard heart failure therapy improved heart function and the clinical condition by moderating the inflammatory processes in patients with HFrEF