Papers by Raffaella Rastaldo
Description: Lo scopo generale di questo testo è quello di offrire una presentazione integrata de... more Description: Lo scopo generale di questo testo è quello di offrire una presentazione integrata dei vari aspetti della fisiologia cardiovascolare. L’integrazione riguarda anche le parti di ogni singolo capitolo in modo che il lettore sia utilmente seguito nell’ apprendimento. Accanto a questa impostazione, gli autori hanno anche cercato di fornire alcuni aggiornamenti collegandoli con le nozioni ormai consolidate. Per adeguarsi al piano prefissato, il libro descrive la fisiologia del cuore dalla struttura alla funzione. Di conseguenza l’elettrofisiologia è illustrata con lo scopo di chiarire le proprietà dei tessuti funzionale del cuore, vale a dire l’automatismo, la conduttività, l’eccitabilità e la contrattilità, quest’ultima vista come base dell’emodinamica. Inoltre la fisiologia del cuore è trattata negli aspetti che la collegano al postcarico arterioso, alla gettata e al ritorno venoso in condizioni normali e patologiche. Un’efficace integrazione delle varie parti richiede ovvia...
Biomedicines, 2022
Human mesenchymal stem cell (hMSC)-based therapy is an emerging resource in regenerative medicine... more Human mesenchymal stem cell (hMSC)-based therapy is an emerging resource in regenerative medicine. Despite the innate ability of hMSCs to migrate to sites of injury, homing of infused hMSCs to the target tissue is inefficient. It was shown that silica nanoparticles (SiO2-NPs), previously developed to track the stem cells after transplantation, accumulated in lysosomes leading to a transient blockage of the autophagic flux. Since CXCR4 turnover is mainly regulated by autophagy, we tested the effect of SiO2-NPs on chemotactic migration of hMSCs along the SDF1α/CXCR4 axis that plays a pivotal role in directing MSC homing to sites of injury. Our results showed that SiO2-NP internalization augmented CXCR4 surface levels. We demonstrated that SiO2-NP-dependent CXCR4 increase was transient, and it reversed at the same time as lysosomal compartment normalization. Furthermore, the autophagy inhibitor Bafilomycin-A1 reproduced CXCR4 overexpression in control hMSCs confirming the direct effect...
Bollettino della Società italiana di biologia sperimentale, 2021
Prof. Losano was born on July the 25th 1934, and he graduated in Medicine and Surgery on November... more Prof. Losano was born on July the 25th 1934, and he graduated in Medicine and Surgery on November 18th 1959. He started his university career in the early 60ties as “Assistente Volontario alla Cattedra di Fisiologia”. He was several times a Visiting Professor at the A.M. Dogliotti College of Medicine of the University of Liberia in Monrovia (Liberia), where he also served as Dean of the Medicine Faculty. In 1973 he was named full professor and he continued to work at Torino University until 2019 as Professor Emeritus.
International Journal of Molecular Sciences, 2021
Myocardial infarction (MI) is one of the leading causes of heart-related deaths worldwide. Follow... more Myocardial infarction (MI) is one of the leading causes of heart-related deaths worldwide. Following MI, the hypoxic microenvironment triggers apoptosis, disrupts the extracellular matrix and forms a non-functional scar that leads towards adverse left ventricular (LV) remodelling. If left untreated this eventually leads to heart failure. Besides extensive advancement in medical therapy, complete functional recovery is never accomplished, as the heart possesses limited regenerative ability. In recent decades, the focus has shifted towards tissue engineering and regenerative strategies that provide an attractive option to improve cardiac regeneration, limit adverse LV remodelling and restore function in an infarcted heart. Acellular scaffolds possess attractive features that have made them a promising therapeutic candidate. Their application in infarcted areas has been shown to improve LV remodelling and enhance functional recovery in post-MI hearts. This review will summarise the upd...
Nanomaterials, 2020
To deliver on the promise of cardiac regeneration, an integration process between an emerging fie... more To deliver on the promise of cardiac regeneration, an integration process between an emerging field, nanomedicine, and a more consolidated one, tissue engineering, has begun. Our work aims at summarizing some of the most relevant prevailing cases of nanotechnological approaches applied to tissue engineering with a specific interest in cardiac regenerative medicine, as well as delineating some of the most compelling forthcoming orientations. Specifically, this review starts with a brief statement on the relevant clinical need, and then debates how nanotechnology can be combined with tissue engineering in the scope of mimicking a complex tissue like the myocardium and its natural extracellular matrix (ECM). The interaction of relevant stem, precursor, and differentiated cardiac cells with nanoengineered scaffolds is thoroughly presented. Another correspondingly relevant area of experimental study enclosing both nanotechnology and cardiac regeneration, e.g., nanoparticle applications i...
Nanomedicine (London, England), May 1, 2018
To assess functional effects of silica nanoparticles (SiO-NPs) on human mesenchymal stem cell (hM... more To assess functional effects of silica nanoparticles (SiO-NPs) on human mesenchymal stem cell (hMSC) cardiac integration potential. SiO-NPs were synthesized and their internalization effects on hMSCs analyzed with particular emphasis on interaction of hMSCs with the cardiac environment Results: SiO-NP internalization affected the area and maturation level of hMSC focal adhesions, accounting for increased in vitro adhesion capacity and augmented engraftment in the myocardial tissue upon cell injection in infarcted isolated rat hearts. SiO-NP treatment also enhanced hMSC expression of Connexin-43, favoring hMSC interaction with cocultured cardiac myoblasts in an ischemia-like environment. These findings provide strong evidence that SiO-NPs actively engage in mediating biological effects, ultimately resulting in augmented hMSC acute cardiac integration potential.
Polish Archives of Internal Medicine, 2016
Sport Sciences for Health, 2015
Anyone can freely access the full text of works made available as "Open Access". Works made avail... more Anyone can freely access the full text of works made available as "Open Access". Works made available under a Creative Commons license can be used according to the terms and conditions of said license. Use of all other works requires consent of the right holder (author or publisher) if not exempted from copyright protection by the applicable law.
Food & Function, 2015
α-Linolenic acid (ALA)-enriched diet prevented isoproterenol (ISO)-induced fibrosis in the ventri... more α-Linolenic acid (ALA)-enriched diet prevented isoproterenol (ISO)-induced fibrosis in the ventricular myocardium.
Journal of physiology and pharmacology : an official journal of the Polish Physiological Society, 2010
Nitric oxide (NO) and reactive oxygen species (ROS) are double-edged swords in reperfused hearts.... more Nitric oxide (NO) and reactive oxygen species (ROS) are double-edged swords in reperfused hearts. The effects of a NO-donor and an antioxidant compound against ischemia/reperfusion were studied. The compounds were tested separately, as a mixture and as a new hybrid molecule containing both leads. Isolated rat hearts underwent 30 min global ischemia and 2 hrs reperfusion. Compounds were infused either at 1 or 10 microM concentrations during the first 20 min of reperfusion. Hybrid was also tested in the presence of mitochondrial K(+) ATP-sensitive (mKATP) channel blockade by 5-HD (100 microM). Reduction of infarct size and recovery of left ventricular developed pressure during reperfusion were evaluated. When given at 1 microM concentration, hybrid significantly improved all indices of protection; its beneficial effects were abolished by mKATP channel blockade. At the same concentration, mixture and NO-donor alone improved recovery of left ventricular developed pressure but did not re...
Heart Failure Reviews, 2015
Apelin is an endogenous peptide acting on the APJ receptor. It consists of several isoforms chara... more Apelin is an endogenous peptide acting on the APJ receptor. It consists of several isoforms characterised by different numbers of aminoacids. The number of aminoacids in the active isoforms range from 36 to 12. Apelin-13 and, to a lesser extent, apelin-36 are considered the most active isoforms with the greatest activity on the cardiovascular homeostasis. The effects normally exerted by the basal level of endogenous apelin, can be enhanced not only by its up-regulation, but may also by its exogenous administration. The present review considers the effects of apelin on various aspects of the cardiovascular function, such as cardiac development, vasomotor tone, angiogenesis, myocardial inotropy in healthy and failing hearts as well as the prevention of ischemia-reperfusion injury, cardiac fibrosis and remodeling. Also the biphasic changes of apelin level during the evolution of heart failure are considered. Although the positive inotropic effect exerted by apelin in normal and failing hearts would suggest the use of this peptide in the treatment of heart failure, the limited duration and extent of its effect do not support this possibility, unless a long lasting (6 hours) infusion is performed to overcome the limit of its short life. However, although the data on the characteristics of the inotropic activity do not provide a strong support for the treatment of active heart failure, apelin may be used in the prevention of heart failure because of its activity in limiting the consequences of myocardial ischemia such as infarct size and cardiac remodeling.
Proceedings of the National Academy of Sciences, 2005
The ability of cardiac stem cells (CSCs) to promote myocardial repair under clinically relevant c... more The ability of cardiac stem cells (CSCs) to promote myocardial repair under clinically relevant conditions (i.e., when delivered intravascularly after reperfusion) is unknown. Thus, rats were subjected to a 90-min coronary occlusion; at 4 h after reperfusion, CSCs were delivered to the coronary arteries via a catheter positioned into the aortic root. Echocardiographic analysis showed that injection of CSCs attenuated the increase in left ventricular (LV) end-diastolic dimensions and impairment in LV systolic performance at 5 weeks after myocardial infarction. Pathologic analysis showed that treated hearts exhibited a smaller increase in LV chamber diameter and volume and a higher wall thickness-to-chamber radius ratio and LV mass-to-chamber volume ratio. CSCs induced myocardial regeneration, decreasing infarct size by 29%. A diploid DNA content and only two chromosomes 12 were found in new cardiomyocytes, indicating that cell fusion did not contribute to tissue reconstitution. In co...
Journal of Cellular and Molecular Medicine, 2008
The last few years have seen a surge of interest for the possibility to use stem cell (SC) transp... more The last few years have seen a surge of interest for the possibility to use stem cell (SC) transplants to repair damaged hearts [1-5]. A wide range of stem/progenitor cell types have been used for cardiac cell therapy, including myoblasts and bone marrow SCs [3, 6]. However, very little is known about the early features of the homing of SC in the receiving heart. In a recent review, Dimmeler et al. [6] states that 'the mechanisms for progenitor cells' homing to sites of tissue injury are only understood rudimentarily'. In particular, nothing is known about early (first few hours) cell survival and distribution in
Journal of Cardiovascular Pharmacology, 2012
Low concentrations of a hydrophilic nitric oxide donor (NOD) are reported to reduce myocardial re... more Low concentrations of a hydrophilic nitric oxide donor (NOD) are reported to reduce myocardial reperfusion injury only when combined with a lipophilic antioxidant (AOX) to form a hybrid molecule (HYB). Here we tested whether liposoluble NOD requires to be combined with AOX to be protective. Isolated rat hearts underwent 30 minutes of ischemia and 120 minutes of reperfusion. To induce postconditioning, 1 mM solutions of the following liposoluble compounds were given during the first 20 minutes of reperfusion: NOD with weak (w-NOD) or strong NO-releasing potency (s-NOD); weak HYB built up with w-NOD and a per se ineffective AOX lead; strong HYB built up with s-NOD and the same AOX; mixtures of w-NOD plus AOX or s-NOD plus AOX. A significant reduction of infarct size with improved recovery of cardiac function was obtained only with weak HYB. We suggest that w-NOD requires the synergy with a per se ineffective AOX to protect. The synergy is possible only if the 2 moieties enter the cell simultaneously as a hybrid, but not as a mixture. It seems that strong HYB was ineffective because an excessive intracellular NO release produces a large amount of reactive species, as shown from the increased nitrotyrosine production.
G Ital …, 2006
Post-ischemic reperfusion worsens myocardial injury. Ischemic preconditioning limits the damage b... more Post-ischemic reperfusion worsens myocardial injury. Ischemic preconditioning limits the damage by ischemia and reperfusion. Both adenosine and nitricoxide (NO) pathways are involved in protection. Preconditioning, however, is of little, if any, practical use as the onset of an infarction is usually impredictable. Recently, it has been shown that the heart can be protected against the extension of reperfusion injuries if 3 or 4 brief (10-30 s) coronary occlusions are performed just at the beginning of the reperfusion. This procedure has been called post-conditioning. Post-conditioning reduces the oxidantinduced injury; moreover, it attenuates the local inflammatory response to reperfusion. Post-conditioning also activates triggers, signaling pathways and effectors implicated in other cardioprotective maneuvers, such as ischemic and pharmacological preconditioning. Post-conditioning seems to trigger the up-regulation of survival kinases principally known to attenuate the pathogenesis of apoptosis and possibly necrosis. As regards the possibility of pharmacological post-conditioning, several agents have been tested. We are testing NO donor(s), which can reduce infarct size in the rat in the absence of post-conditioning. Since during reperfusion there is a large production of reactive oxygen species, also the effect of administration of an antioxidant compound during reperfusion was studied. In the rat, such a procedure reduced the infarct size to a greater extent than post-conditioning. Moreover, an additive effect of NO donors and antioxidant compounds is possible.
Arzneimittelforschung, 2011
Nitric oxide (NO)-donor antioxidants are a class of polyvalent drugs which is focus of great inte... more Nitric oxide (NO)-donor antioxidants are a class of polyvalent drugs which is focus of great interest today; they are potentially useful for the treatment of many forms of cardiovascular diseases, including the myocardial ischemia/reperfusion (I/R) damage which seems to be due to both a burst of reactive oxygen species (ROS) and a reduced release of NO during reperfusion. In this paper the results of a study on the ability of new NO-donor antioxidants containing the phenol vitamin E substructure and furoxan moiety to attenuate I/R damage are reported. The compounds under study are obtained by combining the phenol moiety (6-hydroxy-2,2,5,7,8-pentamethylchroman) present in vitamin E with differently substituted furoxan substructures endowed with different capacity of NOrelease. Their antioxidant and NO-dependent vasodilator activity are reported. The I/R experiments were performed on isolated rat heart preparations perfused at constant flow. After 20 min of stabilization, global ischemia was obtained by interrupting the perfusion for 30 min. After ischemia the hearts were reperfused for 2 hrs. The compounds were added to the perfusion buffer during the first 20 min of reperfusion. At the end of each experiment, infarct size was measured with nitro-blu tetrazolium. From the results it appears that the limitation of the infarct area is favoured by an appropriate balance between NO-donor and antioxidant properties and that these two actions are synergic.
Clinical and Experimental Pharmacology and Physiology, 2008
1. One hour exposure to hyperoxia has been shown previously to limit a subsequent ischaemia-reper... more 1. One hour exposure to hyperoxia has been shown previously to limit a subsequent ischaemia-reperfusion injury in spontaneously breathing rats. We tested the cardioprotective effect of a shorter period of hyperoxia during mechanical ventilation and the possible contribution of reactive oxygen species (ROS) and mitochondrial ATP-sensitive potassium (mitoK ATP) channels. 2. Mechanically ventilated rats were exposed to normoxia (F i o 2 = 0.3) or hyperoxia (F i o 2 = 1.0) for 30 min and pH, Pco 2 , Po 2 , heart rate, airway and blood pressure were measured at baseline and after 30 min mechanical ventilation. Isolated hearts were subsequently subjected to 30 min ischaemia and 120 min reperfusion. Infarct size and left ventricular end-diastolic pressure (LVEDP), developed pressure (LVDP) and coronary flow (CF) were measured. In order to investigate the role of ROS and K ATP channels within the mechanism leading to cardioprotection, the free radical scavenger N-acetylcysteine (NAC; 150 mg/kg) was infused in mechanically ventilated rats and the K ATP channel blockers glibenclamide (200 mmol/L) or 5-hydroxydecanoate (10 mmol/L) were infused in isolated hearts immediately before ischaemia. 3. No differences were detected in Pco 2 , pH, heart rate, airway and blood pressure between the groups. However, the Po 2 in hyperoxic groups was significantly higher compared with that in normoxic groups (P < 0.01). After 30 min ischaemia, we found that hyperoxic preconditioning significantly improved CF (P < 0.01), LVDP (P < 0.01) and LVEDP (P < 0.01) and reduced the extent of infarct size in the reperfused heart compared with the normoxic group (P < 0.01). When rats were pretreated either with NAC before hyperoxic ventilation or with K ATP channel blockers before ischaemia, myocardial protection was abolished. 4. Hyperoxic mechanical ventilation, prior to ischaemia, reduces myocardial reperfusion injury. This is likely to occur through the induction of oxidative stress, which leads to myocyte mitoK ATP channel opening.
Circulation Research, 2008
Ischemic heart disease is characterized chronically by a healed infarct, foci of myocardial scarr... more Ischemic heart disease is characterized chronically by a healed infarct, foci of myocardial scarring, cavitary dilation, and impaired ventricular performance. These alterations can only be reversed by replacement of scarred tissue with functionally competent myocardium. We tested whether cardiac progenitor cells (CPCs) implanted in proximity of healed infarcts or resident CPCs stimulated locally by hepatocyte growth factor and insulin-like growth factor-1 invade the scarred myocardium and generate myocytes and coronary vessels improving the hemodynamics of the infarcted heart. Hepatocyte growth factor is a powerful chemoattractant of CPCs, and insulin-like growth factor-1 promotes their proliferation and survival. Injection of CPCs or growth factors led to the replacement of ≈42% of the scar with newly formed myocardium, attenuated ventricular dilation and prevented the chronic decline in function of the infarcted heart. Cardiac repair was mediated by the ability of CPCs to synthesi...
Circulation Research, 2005
High-mobility group box 1 protein (HMGB1) is a chromatin protein that is released by inflammatory... more High-mobility group box 1 protein (HMGB1) is a chromatin protein that is released by inflammatory and necrotic cells. Extracellular HMGB1 signals tissue damage, stimulates the secretion of proinflammatory cytokines and chemokines, and modulates stem cell function. The present study examined exogenous HMGB1 effect on mouse left-ventricular function and myocyte regeneration after infarction. Myocardial infarction was induced in C57BL/6 mice by permanent coronary artery ligation. After 4 hours animals were reoperated and 200 ng of purified HMGB1 was administered in the peri-infarcted left ventricle. This intervention resulted in the formation of new myocytes within the infarcted portion of the wall. The regenerative process involved the proliferation and differentiation of endogenous cardiac c-kit + progenitor cells. Circulating c-kit + cells did not significantly contribute to HMGB1-mediated cardiac regeneration. Echocardiographic and hemodynamic parameters at 1, 2, and 4 weeks demons...
Circulation Research, 2005
Cardiac stem cells and early committed cells (CSCs-ECCs) express c-Met and insulin-like growth fa... more Cardiac stem cells and early committed cells (CSCs-ECCs) express c-Met and insulin-like growth factor-1 (IGF-1) receptors and synthesize and secrete the corresponding ligands, hepatocyte growth factor (HGF) and IGF-1. HGF mobilizes CSCs-ECCs and IGF-1 promotes their survival and proliferation. Therefore, HGF and IGF-1 were injected in the hearts of infarcted mice to favor, respectively, the translocation of CSCs-ECCs from the surrounding myocardium to the dead tissue and the viability and growth of these cells within the damaged area. To facilitate migration and homing of CSCs-ECCs to the infarct, a growth factor gradient was introduced between the site of storage of primitive cells in the atria and the region bordering the infarct. The newly-formed myocardium contained arterioles, capillaries, and functionally competent myocytes that with time increased in size, improving ventricular performance at healing and long thereafter. The volume of regenerated myocytes was 2200 μm 3 at 16 ...
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Papers by Raffaella Rastaldo