High Density Lipoprotein (HDL) particles, beyond serving as lipid transporters and playing a key role in reverse cholesterol transport, carry a highly variable number of proteins, micro-RNAs, ...vitamins, and hormones, which endow them with the ability to mediate a plethora of cellular and molecular mechanisms that promote cardiovascular health. It is becoming increasingly evident, however, that the presence of cardiovascular risk factors and co-morbidities alters HDLs cargo and protective functions. This concept has led to the notion that metrics other than HDL-cholesterol levels, such as HDL functionality and composition, may better capture HDL cardiovascular protection. On the other hand, the potential of HDL as natural delivery carriers has also fostered the design of engineered HDL-mimetics aiming to improve HDL efficacy or as drug-delivery agents with therapeutic potential. In this paper, we first provide an overview of the molecules known to be transported by HDL particles and mainly discuss their functions in the cardiovascular system. Second, we describe the impact of cardiovascular risk factors and co-morbidities on HDL remodeling. Finally, we review the currently developed HDL-based approaches.
Atherosclerosis is a complex disease in which many processes contribute to lesion development. Yet, it is well accepted that high serum levels of low‐density lipoproteins (LDL) play a main role in ...the initiation and progression of atherosclerosis. Despite currently available optimal LDL‐lowering therapies, a worrisome number of clinical events still occur. The protective effect of high‐density lipoproteins (HDL) in atherosclerosis, either by suppressing vascular‐LDL accumulation, inflammation, oxidation, endothelial damage, and thrombosis, has supported the need of the use of HDL‐raising therapies to address this residual risk. Results obtained in some studies, however, have shown that HDL quality, rather than quantity, should be the target of future pharmacological therapies. Here, we will first explore the mechanism by which excess LDL is fundamental in the development of atherosclerosis and its thrombotic complications, behaving as a factor that introduces chaos in the vascular wall. Afterwards, we will explore how functional HDL, through various cellular and molecular mechanisms, facilitates the resolution of this vascular chaos by suppression of atherosclerosis progression and induction of regression.
Platelets exert fundamental roles in thrombosis, inflammation, and angiogenesis, contributing to different pathologies from cardiovascular diseases to cancer. We previously reported that platelets ...release extracellular vesicles (pEVs) which contribute to thrombus formation. However, pEV composition remains poorly defined. Indeed, pEV quality and type, rather than quantity, may be relevant in intravascular cross-talk with either circulating or vascular cells. We aimed to define the phenotypic characteristics of pEVs released spontaneously and those induced by thrombin activation to better understand their role in disease dissemination. pEVs obtained from washed platelets from healthy donor blood were characterized by flow cytometry. pEVs from thrombin-activated platelets (T-pEVs) showed higher levels of P-selectin and active form of glycoprotein IIb/IIIa than baseline non-activated platelets (B-pEVs). Following mass spectrometry-based differential proteomic analysis, significant changes in the abundance of proteins secreted in T-pEVs compared to B-pEVs were found. These differential proteins were involved in coagulation, adhesion, cytoskeleton, signal transduction, metabolism, and vesicle-mediated transport. Interestingly, release of proteins relevant for cell adhesion, intrinsic pathway coagulation, and platelet activation signalling was significantly modified by thrombin stimulation. A novel pEV-associated protein (protocadherin-α4) was found to be significantly reduced in T-pEVs showing a shift towards increased expression in the membranes of activated platelets. In summary, platelet activation induced by thrombin triggers the shedding of pEVs with a complex proteomic pattern rich in procoagulant and proadhesive proteins. Crosstalk with other vascular and blood cells in a paracrine regulatory mode could extend the prothrombotic signalling as well as promote proteostasic changes in other cellular types.
C-reactive protein (CRP) is a short pentraxin mainly found as a pentamer in the circulation, or as non-soluble monomers CRP (mCRP) in tissues, exerting different functions. This review is focused on ...discussing the role of CRP in cardiovascular disease, including recent advances on the implication of CRP and its forms specifically on the pathogenesis of atherothrombosis and angiogenesis. Besides its role in the humoral innate immune response, CRP contributes to cardiovascular disease progression by recognizing and binding multiple intrinsic ligands. mCRP is not present in the healthy vessel wall but it becomes detectable in the early stages of atherogenesis and accumulates during the progression of atherosclerosis. CRP inhibits endothelial nitric oxide production and contributes to plaque instability by increasing endothelial cell adhesion molecules expression, by promoting monocyte recruitment into the atheromatous plaque and by enzymatically binding to modified low-density lipoprotein. CRP also contributes to thrombosis, but depending on its form it elicits different actions. Pentameric CRP has no involvement in thrombogenesis, whereas mCRP induces platelet activation and thrombus growth. In addition, mCRP has apparently contradictory pro-angiogenic and anti-angiogenic effects determining tissue remodeling in the atherosclerotic plaque and in infarcted tissues. Overall, CRP contributes to cardiovascular disease by several mechanisms that deserve an in-depth analysis.
Recent data have indicated that the myocardium may act as an immune organ initiating cardiac innate immune response and inflammation. It has been suggested that activation of the immune system occurs ...upon the interaction of damage-associated molecular patterns (DAMPs) generated and released during ischemic damage with pattern recognition receptors (Toll like receptors; TLR) present in cardiac cells. Among TLRs, TLR4, and TLR2 are the ones mostly expressed in cardiac tissue. Whereas TLR4 has shown to play a detrimental role in myocardial ischemia/reperfusion (I/R) injury, the effect elicited by TLR2 activation remains controversial. Once activated, TLR signaling may occur via the Myd88- and Trif- dependent pathways leading to NFκB and IFN-3 activation, respectively, and subsequent stimulation of pro-inflammatory and immunomodulatory cytokine gene expression. Cytokine release contributes to neutrophils activation, recruitment, adhesion and infiltration to the site of cardiac injury further perpetuating the inflammatory process. This mini-review will focus on the current knowledge regarding the role of the heart in inducing and coordinating the innate inflammatory response via the TLR signaling pathway in myocardial I/R injury.
Phytosterols and Inflammation Vilahur, Gemma; Ben-Aicha, Soumaya; Diaz-Riera, Elisa ...
Current medicinal chemistry,
01/2019, Letnik:
26, Številka:
37
Journal Article
Recenzirano
Besides the well-characterized effect of foods and supplements enriched with plant sterols/stanols on serum LDL-C concentrations, evidence is now emerging that phytosterols exert beneficial effects ...on non-lipid variables such as inflammatory and oxidative stress markers, coagulation parameters and endothelial function. This makes sterols and stanols an attractive alternative for dietary interventions in cardiovascular disease prevention, particularly in populations at low or medium risk. This review aims to summarize the current knowledge derived from experimental studies and human data on the anti-inflammatory effects of phytosterols/stanols and their relevance in promoting atheroprotection and preventing cardiovascular disease. The anti-inflammatory effects induced by plant sterols/stanols have been demonstrated in in vitro studies and in experimental animal models. However, not all the beneficial effects seen at an experimental level have translated into clinical benefit. Indeed, clinical studies that evaluate the association between phytosterols consumption and inflammatory variables (CRP and cytokines) are inconsistent and have not yet provided a solid answer. Plant sterols have been proposed as useful adjuncts to statin therapy to further reduce the risk of cardiovascular disease. However, there is limited available data and more research needs to be done.
The success of therapies targeting myocardial reperfusion injury is limited, while the cardioprotective impact of mitigating ischemia-related damage remains less explored. We have recently shown in a ...pig model that the intravenous administration of a modified atorvastatin preparation during ischemia attenuates the rise of cardiac ischemia injury biomarkers. In the following study, we sought to investigate the mechanisms behind these ischemia-related cardioprotective effects. Ischemia was induced by 90 min total coronary balloon occlusion in pigs fed a normocholesterolemic regime. Fifteen minutes after the onset of ischemia, animals were randomized to receive intravenous atorvastatin preparation (IV-atorva) or vehicle. After ischemia animals were euthanized to assess the effect of IV-atorva treatment on gene and protein levels/activation of senescence-, apoptosis-, and cardioprotective/metabolic-related markers. Proof-of-concept studies were carried out in mice and rats in which treatments or vehicle were administered 15 min after initiation of ischemia induced by permanent coronary ligation. Western-blot analyses revealed that in the ischemic myocardium of IV-atorva-treated pigs, RhoA was inactivated, phosphorylation of p53 and caspase-3 was reduced and AMPK was activated with the consequent regulation of the mTOR/raptor-signaling pathway. IV-atorva-treated rats showed, as compared to vehicle, a significant reduction (60%) in scar size assessed at 1 month by histological staining, and mice studies demonstrated the causal involvement of AMPK activation in IV-atorva mediated cardioprotective effects. We demonstrate in pigs and rodents that prompt intravenous treatment with atorvastatin during ischemia limits cardiac cell death and reduces infarct size through AMPK signaling.
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