Biomedical subjects

Roberto Bolli

Publications and source records attributed to Roberto Bolli.

77 records · Page 5Linked to original sources

PubMed2002

Role of Src protein tyrosine kinases in late preconditioning against myocardial infarction.

Although Src protein tyrosine kinases (PTKs) have been shown to be essential in late preconditioning (PC) against myocardial stunning, their role in triggering versus mediating late PC against myocardial infarction remains unclear. Four groups of conscious rabbits were subjected to a 30-min coronary occlusion on day 2, with or without PC ischemia on day 1. Administration of the Src PTK inhibitor lavendustin A (LD-A; 1 mg/kg iv) before the PC ischemia on day 1 (group III, n = 7) failed to block the delayed protective effect against myocardial infarction 24 h later. Late PC against infarction, however, was completely abrogated when LD-A was given 24 h after the PC ischemia, prior to the 30-min occlusion on day 2 (group IV, n = 8). We conclude that, in conscious rabbits, Src PTK activity is necessary for the mediation of late PC protection against myocardial infarction on day 2, but not for the initiation of this phenomenon on day 1. Taken together with previous studies in the setting of stunning, these findings reveal heretofore unrecognized differences in the roles of Src PTKs in late PC against stunning versus late PC against infarction.

Animals↗

PubMed2002

Oxidant species trigger late preconditioning against myocardial stunning in conscious rabbits.

Conscious rabbits underwent six 4-min occlusion and 4-min reperfusion cycles for 3 consecutive days (day 1, 2, and 3); on day 1, rabbits received intravenous vehicle [preconditioning (PC)] (group I, n = 6), superoxide dismutase (SOD; group II, n = 5), catalase (group III, n = 6), or the hydroxyl radical (. OH) and peroxynitrite (ONOO-)) scavenger N-2-mercaptopropionyl glycine (MPG [group IV], n = 6). In the PC group, the recovery of systolic wall thickening (WTh) after the sixth reperfusion was markedly improved on days 2 and 3 compared with day 1 and the total deficit of WTh was correspondingly reduced, indicating a late PC effect against myocardial stunning. Neither SOD nor catalase had any significant effect on the severity of stunning on day 1 or on the development of late PC on days 2 and 3, despite high plasma levels. In contrast, MPG markedly attenuated the severity of stunning on day 1 and prevented the development of late PC on day 2. Two additional groups of rabbits received an intracoronary infusion of vehicle (group V, n = 4) or the reactive oxygen species (ROS) generating solution [cumene hydroperoxide (CuOOH, group VI, n = 7)] on day 0, and were then subjected to the six occlusion/reperfusion cycles on days 1, 2, and 3. In group VI, infusion of CuOOH elicited a late PC effect 24 h later (on day 1). Taken together, these results demonstrate that oxidant species play an essential role in triggering the development of late PC against stunning in conscious rabbits. The fact that late PC was blocked by MPG and mimicked by CuOOH implicate ONOO- and/or .OH as the oxygen species responsible for the initiation of this phenomenon. In addition, the finding that exogenous ROS (CuOOH) reproduced the phenotype of late PC indicates that ROS are not only necessary but also sufficient to trigger this defensive adaptation of the heart to stress.

Animals↗

PubMed2002

Formation of protein kinase C(epsilon)-Lck signaling modules confers cardioprotection.

The epsilon isoform of protein kinase C (PKCepsilon) is a member of the PKC family of serine/threonine kinases and plays a critical role in protection against ischemic injury in multiple organs. Functional proteomic analyses of PKCepsilon signaling show that this isozyme forms multiprotein complexes in the heart; however, the precise signaling mechanisms whereby PKCepsilon orchestrates cardioprotection are poorly understood. Here we report that Lck, a member of the Src family of tyrosine kinases, forms a functional signaling module with PKCepsilon. In cardiac cells, PKCepsilon interacts with, phosphorylates, and activates Lck. In vivo studies showed that cardioprotection elicited either by cardiac-specific transgenic activation of PKCepsilon or by ischemic preconditioning enhances the formation of PKCepsilon-Lck modules. Disruption of these modules, via ablation of the Lck gene, abrogated the infarct-sparing effects of these two forms of cardioprotection, indicating that the formation of PKCepsilon-Lck signaling modules is required for the manifestation of a cardioprotective phenotype. These findings demonstrate, for the first time to our knowledge, that the assembly of a module (PKCepsilon-Lck) is an obligatory step in the signal transduction that results in a specific phenotype. Thus, PKCepsilon-Lck modules may serve as novel therapeutic targets for the prevention of ischemic injury.

Animals↗

PubMedDate not supplied

The role of sodium-hydrogen ion exchange in patients undergoing coronary artery bypass grafting.

Sodium-hydrogen ion exchange (NHE) is one of the principal mechanisms of restoring intracellular pH following ischemia and reperfusion. However, up-regulation of the NHE process results in a compensatory increase in the activity of the sodium-calcium exchanger. Intracellular hypercalcemia, resulting from the exchange of sodium for calcium, precipitates myocardial stunning and cell death. It has been postulated that NHE inhibition can protect the ischemic/reperfused myocardium, and preclinical studies have uniformly supported this concept. The Guard During Ischemia Against Necrosis (GUARDIAN) trial suggested benefits of NHE inhibition in subjects undergoing coronary artery bypass grafting (CABG). The sodium-hydrogen eXchange inhibition to Prevent coronary Events in acute cardiac conDITIONs (EXPEDITION) trial will further explore the use of cariporide in a randomized, controlled trial of CABG subjects at risk of myocardial necrosis.

Anti-Arrhythmia Agents↗

PubMedDate not supplied

The telomere-telomerase axis and the heart.

The preservation of myocyte number and cardiac mass throughout life is dependent on the balance between cell death and cell division. Rapidly emerging evidence indicates that new myocytes can be formed through the activation and differentiation of resident cardiac progenitor cells. The critical issue is the identification of mechanisms that define the aging of cardiac progenitor cells and, ultimately, their inability to replace dying myocytes. The most reliable marker of cellular senescence is the modification of the telomere-telomerase axis, together with the expression of the cell cycle inhibitors p16INK4a and p53. Cellular senescence is characterized by biochemical events that occur within the cell. In this regard, one of the most relevant processes is represented by repeated oxidative stress that may evolve into the activation of the cell death program or result in the development of a senescent phenotype. Thus, the modulation of telomerase activity and the control of telomeric length, together with the attenuation of the formation of reactive oxygen species, may represent important therapeutic tools in regenerative medicine and in prevention of aging and diabetic cardiomyopathies.

Animals↗