A thousand words about microparticles in cardiology

Microparticles (MPs) are membrane vesicles of 0.1-1 \mum in diameter produced mainly by platelets, vascular endothelium and blood cells in response to cell activation and stress factors. MPs can be also released during malignant transformation or apoptosis. The essential step in MP formation is the loss of the cell membrane asymmetric phospholipid distribution as response to the increased intracellular calcium levels. MPs contain, proteins and genetic material (DNA, miRNA, mRNA) which enables them to interact and influence target cell. MPs are considered to be markers of ongoing pathophysiological processes in cardiovascular system, due to their role in inflammation and coagulation

Macrophage activation and polarization in post-infarction cardiac remodeling

Adverse cardiac remodeling leads to impaired ventricular function and heart failure, remaining a major cause of mortality and morbidity in patients with acute myocardial infarction. It have been shown that, even if all the recommended therapies for ST-segment elevation myocardial infarction are performed, one third of patients undergoes progressive cardiac remodeling that represents morphological basis for following heart failure. The need to extend our knowledge about factors leading to different clinical scenarios of myocardial infarction and following complications has resulted in a research of immuno-inflammatory pathways and molecular activities as the basis for post-infarction remodeling. Recently, macrophages (cells of the innate immune system) have become a subject of scientific interest under both normal and pathological conditions. Macrophages, besides their role in host protection and tissue homeostasis, play an important role in pathophysiological processes induced by myocardial infarction. In this article we summarize data about the function of monocytes and macrophages plasticity in myocardial infarction and outline potential role of these cells as effective targets to control processes of inflammation, cardiac remodeling and healing following acute coronary event

Role of thrombin in coronary artery bypass grafting

Thrombin is a multifunctional protease, which has a central role in the development and progression of coronary atherosclerotic lesions and it is a possible mediator of myocardial ischemia-reperfusion injury. Its generation and procoagulant activity are greatly upregulated during cardiopulmonary bypass (CPB). On the other hand, activated protein C, a physiologic anticoagulant that is activated by thrombomodulin-bound thrombin, has been beneficial in various models of ischemia-reperfusion. Therefore, our aim in this study was to test whether thrombin generation or protein C activation during coronary artery bypass grafting (CABG) associate with postoperative myocardial damage or hemodynamic changes. To further investigate the regulation of thrombin during CABG, we tested whether preoperative thrombophilic factors associate with increased CPB-related generation of thrombin or its procoagulant activity. We also measured the anticoagulant effects of heparin during CPB with a novel coagulation test, prothrombinase-induced clotting time (PiCT), and compared the performance of this test with the present standard of laboratory-based anticoagulation monitoring. One hundred patients undergoing elective on-pump CABG were studied prospectively. A progressive increase in markers of thrombin generation (F1+2), fibrinolysis (D-dimer), and fibrin formation (soluble fibrin monomer complexes) was observed during CPB, which was further distinctly propagated by reperfusion after myocardial ischemia, and continued to peak after the neutralization of heparin with protamine. Thrombin generation during reperfusion after CABG associated with postoperative myocardial damage and increased pulmonary vascular resistance. Activated protein C levels increased only slightly during CPB before the release of the aortic clamp, but reperfusion and more significantly heparin neutralization caused a massive increase in activated protein C levels. Protein C activation was clearly delayed in relation to both thrombin generation and fibrin formation. Even though activated protein C associated dynamically with postoperative hemodynamic performance, it did not associate with postoperative myocardial damage. Preoperative thrombophilic variables did not associate with perioperative thrombin generation or its procoagulant activity. Therefore, our results do not favor routine thrombophilia screening before CABG. There was poor agreement between PiCT and other measurements of heparin effects in the setting of CPB. However, lower heparin levels during CPB associated with inferior thrombin control and high heparin levels during CPB associated with fewer perioperative transfusions of blood products. Overall, our results suggest that hypercoagulation after CABG, especially during reperfusion, might be clinically important.Trombiini on hyytymisjärjestelmän keskeinen entsyymi, jolla on tärkeä osuus sepelvaltimotaudin synnyssä ja etenemisessä. Lisäksi trombiini on mahdollinen välittäjäaine hapen puutteeseen ja sen jälkeiseen verenkierron palautumiseen liittyvässä sydänlihasvauriossa. Trombiinin tuotanto ja veren hyytymistä aiheuttava vaikutus lisääntyvät voimakkaasti kehon ulkoisen verenkierron aikana. Aktivoitu proteiini C puolestaan on elimistön luonnollinen hyytymistä estävä aine, eli antikoagulantti, joka aktivoituu trombiinin vaikutuksesta. Tutkimuksen tarkoituksena oli selvittää, liittyvätkö trombiinin tuotanto tai proteiini C:n aktivoituminen sepelvaltimo-ohitusleikkauksen jälkeiseen sydänlihasvaurioon tai verenkierron muutoksiin. Trombiinin säätelyn selvittämiseksi tutkimme lisäksi, lisääntyykö trombiinin tuotanto tai sen vaikutukset potilailla, joilla on veren hyytymistä lisääviä tekijöitä, sekä vertasimme uutta hyytymistutkimusta [prothrombinase-induced clotting time (PiCT)] vakiintuneisiin laboratoriomenetelmiin kliinisesti sydänleikkauksessa käytetyn antikoagulantin, hepariinin, vaikutusten mittaamisessa. Tutkimusaineistona oli sata elektiivistä potilasta, joille tehtiin sepelvaltimo-ohitusleikkaus sydämen pysäytystä ja kehon ulkoista verenkiertoa käyttäen. Trombiinin tuotannon, trombiinin hyytymistä aiheuttavan vaikutuksen ja fibrinolyysin merkkiaineiden (protombiinin fragmenttien F1+2, liukoisten fibriinimonomeerikompleksien ja D-dimeerin) pitoisuudet lisääntyivät voimakkaasti leikkauksen aikana erityisesti sydämen verenkierron palauttamisen jälkeen. Tämän ns. reperfuusiovaiheen trombiinin tuotanto liittyi leikkauksen jälkeiseen keuhkoverenkierron vastuksen kohoamiseen ja leikkauksen jälkeen todettuun sydänlihasvaurioon. Proteiini C aktivoitui viiveellä trombiinin tuotantoon nähden ja aktivoitu proteiini C liittyi leikkauksen jälkeiseen verenkierrolliseen toipumiseen eri tavoin leikkausta edeltävästi ja sen eri vaiheissa. Vaikka perinnöllinen veren hyytymisalttius lisää yleisesti veritulppariskiä, leikkausta edeltävissä tutkimuksissa todettuun hyytymisalttiuteen ei liittynyt lisääntynyttä leikkauksen aikaista hyytymisaktivaatiota. Siitä huolimatta, että erilaisten hepariinin vaikutusten mittaamisessa käytettyjen laboratoriomenetelmien tulosten vastaavuus oli huono, osoitettiin heparinisaation asteen liittyvän kääntäen verensiirtojen tarpeeseen ja hyytymisaktivaatioon. Kaikkiaan tutkimuksessa osoitettiin hyytymisaktivaatiolla olevan haitallisia vaikutuksia sydänleikkauksen yhteydessä

Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis.

Fibroblast growth factors (FGFs) are a family of heparin-binding growth factors. FGFs exert their pro-angiogenic activity by interacting with various endothelial cell surface receptors, including tyrosine kinase receptors, heparan-sulfate proteoglycans, and integrins. Their activity is modulated by a variety of free and extracellular matrix-associated molecules. Also, the cross-talk among FGFs, vascular endothelial growth factors (VEGFs), and inflammatory cytokines/chemokines may play a role in the modulation of blood vessel growth in different pathological conditions, including cancer. Indeed, several experimental evidences point to a role for FGFs in tumor growth and angiogenesis. This review will focus on the relevance of the FGF/FGF receptor system in adult angiogenesis and its contribution to tumor vascularization

α-Enolase, a Multifunctional Protein: Its Role on Pathophysiological Situations

α-Enolase is a key glycolytic enzyme in the cytoplasm of prokaryotic and eukaryotic cells and is considered a multifunctional protein. α-enolase is expressed on the surface of several cell types, where it acts as a plasminogen receptor, concentrating proteolytic plasmin activity on the cell surface. In addition to glycolytic enzyme and plasminogen receptor functions, α-Enolase appears to have other cellular functions and subcellular localizations that are distinct from its well-established function in glycolysis. Furthermore, differential expression of α-enolase has been related to several pathologies, such as cancer, Alzheimer’s disease, and rheumatoid arthritis, among others. We have identified α-enolase as a plasminogen receptor in several cell types. In particular, we have analyzed its role in myogenesis, as an example of extracellular remodelling process. We have shown that α-enolase is expressed on the cell surface of differentiating myocytes, and that inhibitors of α-enolase/plasminogen binding block myogenic fusion in vitro and skeletal muscle regeneration in mice. α-Enolase could be considered as a marker of pathological stress in a high number of diseases, performing several of its multiple functions, mainly as plasminogen receptor. This paper is focused on the multiple roles of the α-enolase/plasminogen axis, related to several pathologies

Endothelial progenitor cells and integrins: adhesive needs

In the last decade there have been multiple studies concerning the contribution of endothelial progenitor cells (EPCs) to new vessel formation in different physiological and pathological settings. The process by which EPCs contribute to new vessel formation in adults is termed postnatal vasculogenesis and occurs via four inter-related steps. They must respond to chemoattractant signals and mobilize from the bone marrow to the peripheral blood; home in on sites of new vessel formation; invade and migrate at the same sites; and differentiate into mature endothelial cells (ECs) and/or regulate pre-existing ECs via paracrine or juxtacrine signals. During these four steps, EPCs interact with different physiological compartments, namely bone marrow, peripheral blood, blood vessels and homing tissues. The success of each step depends on the ability of EPCs to interact, adapt and respond to multiple molecular cues. The present review summarizes the interactions between integrins expressed by EPCs and their ligands: extracellular matrix components and cell surface proteins present at sites of postnatal vasculogenesis. The data summarized here indicate that integrins represent a major molecular determinant of EPC function, with different integrin subunits regulating different steps of EPC biology. Specifically, integrin α4β1 is a key regulator of EPC retention and/or mobilization from the bone marrow, while integrins α5β1, α6β1, αvβ3 and αvβ5 are major determinants of EPC homing, invasion, differentiation and paracrine factor production. β2 integrins are the major regulators of EPC transendothelial migration. The relevance of integrins in EPC biology is also demonstrated by many studies that use extracellular matrix-based scaffolds as a clinical tool to improve the vasculogenic functions of EPCs. We propose that targeted and tissue-specific manipulation of EPC integrin-mediated interactions may be crucial to further improve the usage of this cell population as a relevant clinical agent

Drug treatment of hypertension: focus on vascular health

Hypertension, the most common preventable risk factor for cardiovascular disease and death, is a growing health burden. Serious cardiovascular complications result from target organ damage including cerebrovascular disease, heart failure, ischaemic heart disease and renal failure. While many systems contribute to blood pressure (BP) elevation, the vascular system is particularly important because vascular dysfunction is a cause and consequence of hypertension. Hypertension is characterised by a vascular phenotype of endothelial dysfunction, arterial remodelling, vascular inflammation and increased stiffness. Antihypertensive drugs that influence vascular changes associated with high BP have greater efficacy for reducing cardiovascular risk than drugs that reduce BP, but have little or no effect on the adverse vascular phenotype. Angiotensin converting enzyme ACE inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) improve endothelial function and prevent vascular remodelling. Calcium channel blockers also improve endothelial function, although to a lesser extent than ACEIs and ARBs. Mineralocorticoid receptor blockers improve endothelial function and reduce arterial stiffness, and have recently become more established as antihypertensive drugs. Lifestyle factors are essential in preventing the adverse vascular changes associated with high BP and reducing associated cardiovascular risk. Clinicians and scientists should incorporate these factors into treatment decisions for patients with high BP, as well as in the development of new antihypertensive drugs that promote vascular health