Atherosclerosis is the major underlying pathology of cardiovascular diseases that together are the leading cause of death worldwide. The formation of atherosclerotic plaques is driven by chronic vascular inflammation. Although several risk factors have been identified and significant progress in disease prevention and treatment has been made, no therapeutic agents targeting inflammation are clinically available. Recent clinical trials established the potential of anti-inflammatory therapies as a treatment of atherosclerosis. However, adverse impacts on host defense have raised safety concerns about these therapies. Scientific evidence during the past 40 years implicated an adaptive immune response against plaque-associated autoantigens in atherogenesis. Preclinical data have underscored the protective potential of immunization against such targets precisely and without the impairment of host defense. In this review, we discuss the current vaccination strategies against atherosclerosis, supposed mechanisms of action, therapeutic potential, and the challenges that must be overcome in translating this idea into clinical practice.
Marfan syndrome (MFS) is a prevalent inherited connective tissue disorder associated with premature mortality due to thoracic aortic aneurysms and subsequent fatal aortic events. Current treatment options improve outcomes only partially and better preventive pharmacotherapies are needed. By utilizing patient samples and animal disease models, we herein demonstrate that leukocyte-derived myeloperoxidase (MPO) critically contributes to disease progression. MFS patients and mice displayed increased circulating MPO levels as well as marked aortic MPO deposition compared to controls. Mechanistically, MPO induced inflammatory endothelial activation and endothelial-to-mesenchymal transition which triggered aortic leukocyte recruitment. Furthermore, MPO directly contributed to adverse extracellular matrix remodeling by promoting oxidative stress and nitrosylation of extracellular matrix proteins. Genetic MPO deficiency and pharmacological MPO inhibition attenuated MFS-related aneurysm formation. We herein identify MPO as a critical mediator of MFS-related thoracic aortic aneurysm formation and a promising target to influence disease progression.
Background Acute coronary syndromes (ACS) remain the most devastating clinical manifestation of cardiovascular disease, the most common cause of global mortality. ACS frequently arises from rupture of the coronary fibrous cap, in which a highly thrombogenic necrotic core is exposed to circulating blood, thereby triggering thrombus formation and impairing myocardial perfusion. While inflammation has been implicated as a key mechanism contributing to atherosclerotic plaque vulnerability and rupture, the underlying mechanisms leading to coronary plaque erosion, another form of ACS, are not well understood. In recent findings, flow cytometric (FACS) analysis of blood from the site of patients with culprit lesion plaque erosion showed significant enrichment of both CD4+ and CD8+ T-lymphocytes (+8.1% and +11.2%, respectively, both P<0.05) as well as effector molecules such as granzyme A (+22.4%), perforin (+58.8%), and granulysin (+75.4%) as compared with patients with plaque rupture culprit lesion. The proximity of eroded lesions to coronary bifurcations seen by optical coherence tomography provides further elucidations linking shear stress alterations to the occurrence of erosional ACS. Purpose We aim to further explore the underlying immune cell mechanisms of coronary plaque erosion via a novel single cell multi-omic approach, never before established from samples aspirated from the arterial sheath. Methods Patients presenting with Myocardial Infarction underwent emergent coronary angiography & percutaneous coronary intervention. Infarction was characterized as either coronary plaque rupture or erosion by optical coherence tomography, in which then blood samples were obtained by being aspirated directly along the arterial sheath. Peripheral blood mononuclear cells were isolated via density gradient within four hours of sample aspiration and cryopreserved. Samples from 24 patients were promptly thawed, washed and incubated with 137 oligonucleotide barcoded antibodies to detect surface protein expression as well as a cellular hashtag antibody. Bioinformatic integration of single cell epitope and transcriptome information was performed derived from custom pipelines. Results Our analysis found 32 unique leukocyte clusters that allowed us to rigorously compare each patients sequenced single cell data -totaling approximately 140,000 singe cells. Additionally, the discovery of T cell oligoclonality amongst certain disease patients alludes to antigen-specific activation. We also observed increased CCL4 expression in CD8+ T-lymphocytes within erosional ACS. Conclusion Our high-parametric immune cell analysis shows distinct differences in the adaptive immune system, particularly CD8+ T-lymphocytes and their effector molecules, in the pathogenesis of erosional versus ruptured ACS. Furthermore, our observations found on the oligoclonal expansion of T cell clones aids us to further elucidate underlying mechanisms of culprit lesion formation in ACS. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): DGK - German Cardiac SocietyDGF - TRR 259 Aortic Disease German Research Foundation
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