Lipid-rich drusen are the sine qua non of age-related macular degeneration (AMD), the leading cause of blindness in older adults in the developed world. Efforts directed at uncovering effective therapeutic strategies have led to the hypothesis that altered lipid metabolism may play a pathogenic role in AMD. This hypothesis is supported by the fact that: (1) drusen, the hallmark histopathologic feature of AMD, are composed of lipids, (2) polymorphisms of genes involved in lipid homeostasis are associated with increased odds of AMD, (3) metabolomics studies show that patients with AMD have alterations in metabolites from lipid pathways, and (4) alterations in serum lipid profiles as a reflection of systemic dyslipidemia are associated with AMD. There is strong evidence that statins, which are well described for treating dyslipidemia and reducing risk associated with cardiovascular disease, may have a role for treating certain cohorts of AMD patients, but this has yet to be conclusively proven. Of interest, the specific changes in serum lipoprotein profiles associated with decreased cardiovascular risk (i.e., high HDL levels) have been shown in some studies to be associated with increased risk of AMD. In this review, we highlight the evidence that supports a role for altered lipid metabolism in AMD and provide our perspective regarding the remaining questions that need to be addressed before lipid-based therapies can emerge for specific cohorts of AMD patients.摘要: 富含脂质的玻璃疣是年龄相关性黄斑变性 (AMD) 的重要特征, AMD是发达国家老年人失明的主要原因。为发现有效的治疗策略提出了一个假说, 即脂质代谢的改变可能在AMD中起致病作用。这一假说目前有以下事实支持: (1) 作为AMD标志性组织病理学特征的玻璃疣是由脂质组成, (2) 参与脂质稳态的基因多态性与AMD的患病几率增加有关, (3) 代谢组学研究表明AMD患者的脂质代谢产物发生了改变, 以及4) 反映全身性血脂异常的血脂谱变化与AMD有关。有强有力的证据表明, 他汀类药物可能在治疗某些AMD患者的队列中发挥作用, 但这一观点尚未得到确凿的证明, 且他汀类药物在治疗血脂异常和降低与心血管疾病相关的风险方面得到了证实。有趣的是, 一些研究表明, 血清脂蛋白谱中与心血管风险降低 (即高密度脂蛋白水平) 相关的特定变化与AMD风险增加有关。在这篇综述中, 我们强调了支持脂质代谢改变在AMD中作用的证据, 并就AMD患者特定队列中在脂质治疗前需要解决的问题提出了我们的观点。. 

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Dyslipidemia in age-related macular degeneration

The Food and Drug Administration has approved Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors for the treatment of dyslipidemia. However, evidence of the optimal PCSK9 agents targeting PCSK9 for secondary prevention in patients with high-risk of cardiovascular events is lacking. Therefore, this study was conducted to evaluate the benefit and safety of different types of PCSK9 inhibitors.Several databases including Cochrane Central, Ovid Medline, and Ovid Embase were searched from inception until March 30, 2022 without language restriction. Randomized controlled trials (RCTs) comparing administration of PCSK9 inhibitors with placebo or ezetimibe for secondary prevention of cardiovascular events in patients with statin-background therapy were identified. The primary efficacy outcome was all-cause mortality. The primary safety outcome was serious adverse events.Overall, nine trials totaling 54,311 patients were identified. Three types of PCSK9 inhibitors were evaluated. The use of alirocumab was associated with reductions in all-cause mortality compared with control (RR 0.83, 95% CrI 0.72-0.95). Moreover, evolocumab was associated with increased all-cause mortality compared with alirocumab (RR 1.26, 95% CrI 1.04-1.52). We also found alirocumab was associated with decreased risk of serious adverse events (RR 0.94, 95% CrI 0.90-0.99).In consideration of the fact that both PCSK9 monoclonal antibody and inclisiran enable patients to achieve recommended LDL-C target, the findings in this meta-analysis suggest that alirocumab might provide the optimal benefits regarding all-cause mortality with relatively lower SAE risks, and evolocumab might provide the optimal benefits regarding myocardial infarction for secondary prevention in patients with high-risk of cardiovascular events. Further head-to-head trials with longer follow-up and high methodologic quality are warranted to help inform subsequent guidelines for the management of these patients. 

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PCSK9 inhibitors for secondary prevention in patients with cardiovascular diseases: a bayesian network meta-analysis

Cardiovascular disease is the leading cause of mortality worldwide. Inflammation has long been established as a key component in the pathophysiology of coronary artery disease. The interleukin-1 family consists of 11 members that regulate the inflammatory response through both pro- and anti-inflammatory properties with the Nod-like receptor (NLR) family pyrin domain containing 3 inflammasome having a pivotal role in the process of converting interleukin-1 beta and interleukin-18, two key inflammatory mediators, into their mature forms. Interleukin-1 affects various cell types that participate in the pathogenesis of atherosclerosis as it enhances the expression of leukocyte adhesion molecules on the surface of endothelial cells augment the permeability of the endothelial cell barrier, attracting monocytes and macrophages into the vessel wall and aids the migration of smooth muscle cells toward atheroma. It also enhances the aggregation of low-density lipoprotein particles in endothelium and smooth muscle cells and exhibits procoagulant activity by inducing synthesis, cell-surface expression and release of tissue factor in endothelial cells, promoting platelet adhesion. The value of interleukin-1 as a diagnostic biomarker is currently limited but interleukin-1 beta, interleukin-18 and interleukin-37 have shown promising data regarding their prognostic value in coronary artery disease. Importantly, target anti-inflammatory treatments have shown promising results regarding atherosclerosis progression and cardiovascular events. In this review article we focus on the immense role of interleukin-1 in atherosclerosis progression, inflammation cascade and in the clinical application of target anti-inflammatory treatments.

Interleukin-1 in Coronary Artery Disease.

Background Graft vascular disease (GVD), which limits the long-term survival of patients after solid-organ transplantation, is associated with both immune responses and nonimmune factors, including dyslipidemia. Recent studies have shown that inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9), a U.S. Federal Drug Administration-approved treatment for hyperlipidemia, reduces cardiovascular events, regulates inflammatory responses, and enhances the efficacy of immune checkpoint therapy in cancer treatment through a cholesterol-independent mechanism. However, whether targeting PCSK9 is a potential therapeutic strategy for GVD remains unknown. Methods Serum samples and grafts were harvested from male mice undergoing abdominal aortic transplantation. The pathological alterations in the aortic grafts were detected by hematoxylin and eosin staining, Verhoeff’s Van Gieson staining, and Masson staining. Inflammatory cell infiltration and proinflammatory cytokine expression in the aortic grafts were detected by immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR), respectively. The regulatory effects of PCSK9 on vascular smooth muscle cell (VSMC) migration and proliferation were examined by transwell, EdU, and western blot assays. The effect of Evolocumab, a PCSK9 inhibitor, on GVD in humanized PCSK9 mice was also evaluated. Results PCSK9 was upregulated in the serum, grafts, and liver of mice in the allograft group subjected to abdominal aortic transplantation. Pcsk9 knockout significantly reduced vascular stenosis, the intimal hyperplasia area and collagen deposition. Pcsk9 depletion also inhibited macrophage recruitment and the mRNA expression of proinflammatory cytokines in aortic grafts. Furthermore, Pcsk9 knockout suppressed the migration and proliferation of VSMCs, which was related to the inhibition of NLRP3 inflammasome activation. Meanwhile, Evolocumab significantly ameliorated GVD in humanized PCSK9 mice. Conclusion PCSK9 is upregulated in a mouse model of GVD, and Pcsk9 knockout reduces vascular occlusion, suggesting that PCSK9 may be a promising target for the treatment of GVD.

https://www.frontiersin.org/articles/10.3389/fimmu.2022.894789/pdf

Targeting PCSK9 Ameliorates Graft Vascular Disease in Mice by Inhibiting NLRP3 Inflammasome Activation in Vascular Smooth Muscle Cells

Abstract Depression has a large burden, but the development of new drugs for its treatment has proved difficult. Progresses in neuroscience have highlighted several physiopathological pathways, notably inflammatory and metabolic ones, likely involved in the genesis of depressive symptoms. A novel strategy proposes to repurpose established medical treatments of known safety and to investigate their potential antidepressant activity. Among numerous candidates, growing evidence suggests that statins may have a positive role in the treatment of depressive disorders, although some have raised concerns about possible depressogenic effects of these widely prescribed medications. This narrative review summarises relevant findings from translational studies implicating many interconnected neurobiological and neuropsychological, cardiovascular, endocrine-metabolic, and immunological mechanisms by which statins could influence mood. Also, the most recent clinical investigations on the effects of statins in depression are presented. Overall, the use of statins for the treatment of depressive symptoms cannot be recommended based on the available literature, though this might change as several larger, methodologically robust studies are being conducted. Nevertheless, statins can already be acknowledged as a driver of innovation in mental health, as they provide a novel perspective to the physical health of people with depression and for the development of more precise antidepressant treatments.

Statins in depression: a repurposed medical treatment can provide novel insights in mental health

Statins are among the most widely used drug classes in the world. Apart from their basic mechanism of action, which is lowering cholesterol levels, many pleiotropic effects have been described so far, such as anti-inflammatory and antiatherosclerotic effects. A growing number of scientific reports have proven that these drugs have a beneficial effect on the functioning of the nervous system. The first reports proving that lipid-lowering therapy can influence the development of neurological and psychiatric diseases appeared in the 1990s. Despite numerous studies about the mechanisms by which statins may affect the functioning of the central nervous system (CNS), there are still no clear data explaining this effect. Most studies have focused on the metabolic effects of this group of drugs, however authors have also described the pleiotropic effects of statins, pointing to their probable impact on the neurotransmitter system and neuroprotective effects. The aim of this paper was to review the literature describing the impacts of statins on dopamine, serotonin, acetylcholine, and glutamate neurotransmission, as well as their neuroprotective role. This paper focuses on the mechanisms by which statins affect neurotransmission, as well as on their impacts on neurological and psychiatric diseases such as Parkinson’s disease (PD), Alzheimer’s disease (AD), vascular dementia (VD), stroke, and depression. The pleiotropic effects of statin usage could potentially open floodgates for research in these treatment domains, catching the attention of researchers and clinicians across the globe.

https://www.mdpi.com/1420-3049/26/10/2838/pdf

The Effects of Statins on Neurotransmission and Their Neuroprotective Role in Neurological and Psychiatric Disorders.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is the last discovered member of the family of proprotein convertases (PCs), mainly synthetized in hepatic cells. This serine protease plays a pivotal role in the reduction of the number of low-density lipoprotein receptors (LDLRs) on the surface of hepatocytes, which leads to an increase in the level of cholesterol in the blood. This mechanism and the fact that gain of function (GOF) mutations in PCSK9 are responsible for causing familial hypercholesterolemia whereas loss-of-function (LOF) mutations are associated with hypocholesterolemia, prompted the invention of drugs that block PCSK9 action. The high efficiency of PCSK9 inhibitors (e.g., alirocumab, evolocumab) in decreasing cardiovascular risk, pleiotropic effects of other lipid-lowering drugs (e.g., statins) and the multifunctional character of other proprotein convertases, were the cause for proceeding studies on functions of PCSK9 beyond cholesterol metabolism. In this article, we summarize the current knowledge on the roles that PCSK9 plays in different tissues and perspectives for its clinical use.

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Insight into the Evolving Role of PCSK9

https://www.mdpi.com/1648-9144/58/5/624/pdf?version=1652081559

Plasma Concentrations of Cytokines in Patients with Combined Hyperlipidemia and Atherosclerotic Plaque before Treatment Initiation—A Pilot Study

Background: In addition to reducing plasma lipids, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors may produce numerous nonlipid-related pleiotropic effects. The purpose of this trial was to determine the efficacy of PCSK9 inhibitors alone in patients with isolated hypercholesterolemia. Methods: The trial enrolled 21 individuals with isolated hypercholesterolemia and atherosclerosis who received alirocumab for 90 days (150 mg every two weeks). Lipids, glucose homeostasis factors, and hemostatic markers were measured in the plasma at baseline and after treatment. Results: The PCSK9 inhibitor administered to these patients reduced plasma levels/activity of fibrinogen (from 3.6 ± 0.5 to 2.9 ± 0.4 g/L, p < 0.01), factor VII (from 143.8 ± 16.7 to 114.5 ± 14.1%, p < 0.01) and plasminogen activator inhibitor-1 (PAI-1) (from 74.9 ± 13.9 to 52.8 ± 9.1 ng/mL, p < 0.001) without a significant reduction in von Willebrand factor levels, and it tended to prolong the partial thromboplastin and prothrombin times. Conclusion: Our findings indicate that treatment with PCSK9 inhibitors has a multipotential effect on fibrinolysis and coagulation in patients with isolated hypercholesterolemia and that this medication may have some future benefits in patients who are statin-intolerant or contraindicated to statin use.

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Effect of PCSK9 Inhibitors on Hemostasis in Patients with Isolated Hypercholesterolemia

Atherosclerosis is a disorder in which, in addition to high cholesterol levels, several plasma factors play a significant role in its development. Among these cytokines and molecules are interleukin 6 (IL-6), interleukin 18 (IL-18), tumor necrosis factor α (TNF-α), metalloproteinase 2 (MMP-2), and metalloproteinase 9 (MMP-9), all of which may contribute to the stabilization of atherosclerotic plaque. The purpose of this study was to determine the effect of advanced lipid-lowering therapy on the levels of these determinants by utilizing proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors in patients with verified high-risk atherosclerotic plaque. Methods: The study involved patients with dyslipidemia who had the presence of unstable atherosclerotic plaque verified by ultrasonography and who were eligible to begin alirocumab treatment. The levels of IL-6, IL, 18, TNF-α, and MMPs were determined in this group before and after three months of therapy. After treatment, a statistically significant decrease in concentrations of Il-18, Il-6, TNF-α (p < 0.001) and MMP-2 (p < 0.05) was observed. Additionally, we observed that the concentrations of these markers were significantly higher in the group of patients prior to initiating therapy than in the control group. Our study’s results suggest that PCSK-9 inhibitor therapy significantly reduces the concentration of factors influencing the stability of atherosclerotic plaque, which may explain their essential importance in reducing cardiovascular risk in patients receiving this treatment.

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Impact of PCSK9 Inhibition on Proinflammatory Cytokines and Matrix Metalloproteinases Release in Patients with Mixed Hyperlipidemia and Vulnerable Atherosclerotic Plaque

Marcin Hachuła

Papers

The Effects of Statins on Neurotransmission and Their Neuroprotective Role in Neurological and Psychiatric Disorders.

Insight into the Evolving Role of PCSK9

Plasma Concentrations of Cytokines in Patients with Combined Hyperlipidemia and Atherosclerotic Plaque before Treatment Initiation—A Pilot Study

Effect of PCSK9 Inhibitors on Hemostasis in Patients with Isolated Hypercholesterolemia

Impact of PCSK9 Inhibition on Proinflammatory Cytokines and Matrix Metalloproteinases Release in Patients with Mixed Hyperlipidemia and Vulnerable Atherosclerotic Plaque