Myocardial ischemia reperfusion injury and cardioprotection in the presence of sensory neuropathy: therapeutic options

During the last decades, mortality of acute myocardial infarction has been dramatically improved, however, the incidence of post-infarction heart failure is still increasing. Cardioprotection by ischemic conditioning have been discovered more than 3 decades ago, however, its clinical translation is still an unmet need, mainly due to the disrupted cardioprotective signalling pathways in the presence of different cardiovascular risk factors and comorbidities and their medications. Sensory neuropathy is one of the comorbidities that has been shown to interfere with cardioprotection. In the present review we summarize the diverse aetiology of sensory neuropathies and the mechanisms by which neuropathies may interfere with ischemic heart disease and cardioprotective signalling. Moreover, we suggest future therapeutic options targeting ischemic heart and sensory neuropathy simultaneously

miR-125b is a protectomiR: A rising star for acute cardioprotection

Myocardial infarction and resulting heart failure remain the leading causes of death worldwide. Therefore, novel therapies are required to protect the heart against the detrimental effects of acute ischemia/reperfusion injury. Micro-RNAs are promising novel targets for cardioprotection as highlighted by recent seminal position papers and reviews (Hausenloy et al., 2017; Varga et al., 2015; Perrino et al., 2017 [1-3])

An Observational Study on the Pharmacokinetics of Oseltamivir in Lactating Influenza Patients

Influenza infection may lead to serious complications in the postpartum period, therefore, oseltamivir treatment in these patients and their breastfed infants is of great importance. However, the pharmacokinetics of oseltamivir in postpartum lactating women with acute influenza infection, and the consequent infant exposure to oseltamivir are still unknown, and these data would help in assessing risk and the need for dose adjustment in breastfed infants

Capsaicin-Sensitive Sensory Nerves and the TRPV1 Ion Channel in Cardiac Physiology and Pathologies

Cardiovascular diseases, including coronary artery disease, ischemic heart diseases such as acute myocardial infarction and postischemic heart failure, heart failure of other etiologies, and cardiac arrhythmias, belong to the leading causes of death. Activation of capsaicin-sensitive sensory nerves by the transient receptor potential vanilloid 1 (TRPV1) capsaicin receptor and other receptors, as well as neuropeptide mediators released from them upon stimulation, play important physiological regulatory roles. Capsaicin-sensitive sensory nerves also contribute to the development and progression of some cardiac diseases, as well as to mechanisms of endogenous stress adaptation leading to cardioprotection. In this review, we summarize the role of capsaicin-sensitive afferents and the TRPV1 ion channel in physiological and pathophysiological functions of the heart based mainly on experimental results and show their diagnostic or therapeutic potentials. Although the actions of several other channels or receptors expressed on cardiac sensory afferents and the effects of TRPV1 channel activation on different non-neural cell types in the heart are not precisely known, most data suggest that stimulation of the TRPV1-expressing sensory nerves or stimulation/overexpression of TRPV1 channels have beneficial effects in cardiac diseases

Cardioprotection by remote ischemic preconditioning of the rat heart is mediated by extracellular vesicles

Remote ischemic preconditioning (RIPC) of the heart is exerted by brief ischemic insults affected on a remote organ or a remote area of the heart before a sustained cardiac ischemia. To date, little is known about the inter-organ transfer mechanisms of cardioprotection by RIPC. Exosomes and microvesicles/microparticles are vesicles of 30-100nm and 100-1000nm in diameter, respectively (collectively termed extracellular vesicles [EVs]). Their content of proteins, mRNAs and microRNAs, render EVs ideal conveyors of inter-organ communication. However, whether EVs are involved in RIPC, is unknown. Therefore, here we investigated whether (1) IPC induces release of EVs from the heart, and (2) EVs are necessary for cardioprotection by RIPC. Hearts of male Wistar rats were isolated and perfused in Langendorff mode. A group of donor hearts was exposed to 3x5-5min global ischemia and reperfusion (IPC) or 30min aerobic perfusion, while coronary perfusates were collected. Coronary perfusates of these hearts were given to another set of recipient isolated hearts. A group of recipient hearts received IPC effluent depleted of EVs by differential ultracentrifugation. Infarct size was determined after 30min global ischemia and 120min reperfusion. The presence or absence of EVs in perfusates was confirmed by dynamic light scattering, the EV marker HSP60 Western blot, and electron microscopy. IPC markedly increased EV release from the heart as assessed by HSP60. Administration of coronary perfusate from IPC donor hearts attenuated infarct size in non-preconditioned recipient hearts (12.9+/-1,6% vs. 25.0+/-2.7%), similarly to cardioprotection afforded by IPC (7.3+/-2.7% vs. 22.1+/-2.9%) on the donor hearts. Perfusates of IPC hearts depleted of EVs failed to exert cardioprotection in recipient hearts (22.0+/-2.3%). This is the first demonstration that EVs released from the heart after IPC are necessary for cardioprotection by RIPC, evidencing the importance of vesicular transfer mechanisms in remote cardioprotection

Stresszválasz: membrántól membránig = Stress response: from membrane to membrane

A 2005-ben befejezett munka során széles kisérleti háttere, különböző sejtes modellekre alapozva szisztematikus munkával igazoltuk az un "membrán szenzor" hipotézis univerzális érvényességét. A stresszfehérje (molekuláris chaperon) válasz sejt- és molekuláris hátterének egy teljesen új aspektusát tártuk fel, amikor is a stresszválasz primér jelképző funkcióját nem a proteotoxicitás, hanem a membránok lipidfázisa által kontrolált állapotváltozások látják el. A membránok lipid-lipid ill. lipid-fehérje kölcsönhatásaiban ("molekuláris kapcsolók") stressz (pld. magashőmérséklet) által kiváltott változásokat a membránok fehérje és lipidösszetételének ill. mikrodomén szintű finomszerveződésének szintjén követtük. Igazoltuk a stresszfehérjék lipidmediálta kölcsönhatásait. Kutatásaink újgenerációs gyógyszerek (pld. hidroximsavszármazékok) kifejlesztését alapozták meg. Ezek a stresszfehérje szintézis megfelelő kontrolljával olyan patológiás állapotok gyógyítását teszik lehetővé, mint a 2. típusú diabétesz, vagy a neurodegeneratív betegségek. | Based on broad experimental approaches and different cellular models in the course of the realization of this OTKA project we provided evidences on the universal validity of the ?membrane sensor? hypothesis. We explored a novel aspect of stress protein response by highlighting those conditions (mild heat stress, membrane defects in disease states, aging, etc.) under which the primary cellular stress sensing mechanism operates by subtle, lipid-phase controlled membrane alterations, rather than by massive proteotoxicity (severe stress). Membrane changes induced by various stress conditions (likely governed by lipid-lipid and lipid-protein interactions) were systematically monitored by real-time single molecule microscopy and coupled to the downstream signaling pathways, leading ultimately to hsp transcription. We have shown, that stress proteins are capable to transport and translocate to the lipid phase of membranes. Our investigations opened the door for the development of a new-generation of drugs. There mode of action is linked to the normalization of dysregulated stress protein response in disease states, like type2 diabetes or neurodegenerative diseases

Preconditioning protects the heart in a prolonged uremic condition

Metabolic diseases such as hyperlipidemia and diabetes attenuate the cardioprotective effect of ischemic preconditioning. In the present study, we examined whether another metabolic disease, prolonged uremia, affects ischemia/reperfusion injury and cardioprotection by ischemic preconditioning. Uremia was induced by partial nephrectomy in male Wistar rats. The development of uremia was verified 29 wk after surgery. Transthoracic echocardiography was performed to monitor cardiac function. At week 30, hearts of nephrectomized and sham-operated rats were isolated and subjected to a 30-min coronary occlusion followed by 120 min reperfusion with or without preceding preconditioning induced by three intermittent cycles of brief ischemia and reperfusion. In nephrectomized rats, plasma uric acid, carbamide, and creatinine as well as urine protein levels were increased as compared with sham-operated controls. Systolic anterior and septal wall thicknesses were increased in nephrectomized rats, suggesting the development of a minimal cardiac hypertrophy. Ejection fraction was decreased and isovolumic relaxation time was shortened in nephrectomized rats demonstrating a mild systolic and diastolic dysfunction. Infarct size was not affected significantly by nephrectomy itself. Ischemic preconditioning significantly decreased infarct size from 24.8 ± 5.2% to 6.6 ± 1.3% in the sham-operated group and also in the uremic group from 35.4 ± 9.5% to 11.9 ± 3.1% of the area at risk. Plasma ANG II and nitrotyrosine were significantly increased in the uremic rats. We conclude that although prolonged experimental uremia leads to severe metabolic changes and the development of a mild myocardial dysfunction, the cardioprotective effect of ischemic preconditioning is still preserved