Inflammation: A Novel Therapeutic Target/Direction in Atherosclerosis

Li, Bin; Li, Weihong; Li, Xiaoli; Zhou, Hong

doi:10.2174/1381612822666161230142931

Cited by 118 publications

(106 citation statements)

References 188 publications

(206 reference statements)

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“…The pathophysiology of AVS can be divided in two phases: An initiation phase and a propagation phase. The initiation phase of AVS precedes calcification and is similar to the pathophysiology of atherosclerosis [32][33][34][35][36]. In the aortic valve, the initiation phase is ignited by damage to the upper cell layer of the valve comprising of valvular endothelial cells (VEC), a process caused by mechanical, oxidative, or shear stress [37].…”

Section: Pathophysiology Of Lp(a)-induced Avsmentioning

confidence: 99%

Lipoprotein(a) as Orchestrator of Calcific Aortic Valve Stenosis

et al. 2019

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Aortic valve stenosis (AVS) is the most prevalent valvular heart disease in the Western World with exponentially increased incidence with age. If left untreated, the yearly mortality rates increase up to 25%. Currently, no effective pharmacological interventions have been established to treat or prevent AVS. The only treatment modality so far is surgical or transcatheter aortic valve replacement (AVR). Lipoprotein(a) [Lp(a)] has been implicated as a pivotal player in the pathophysiology of calcification of the valves. Patients with elevated levels of Lp(a) have a higher risk of hospitalization or mortality due to the presence of AVS. Multiple studies indicated Lp(a) as a likely causal and independent risk factor for AVS. This review discusses the most important findings and mechanisms related to Lp(a) and AVS in detail. During the progression of AVS, Lp(a) enters the aortic valve tissue at damaged sites of the valves. Subsequently, autotaxin converts lysophosphatidylcholine in lysophosphatidic acid (LysoPA) which in turn acts as a ligand for the LysoPA receptor. This triggers a nuclear factor-κB cascade leading to increased transcripts of interleukin 6, bone morphogenetic protein 2, and runt-related transcription factor 2. This progresses to the actual calcification of the valves through production of alkaline phosphatase and calcium depositions. Furthermore, this review briefly mentions potentially interesting therapies that may play a role in the treatment or prevention of AVS in the near future.

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Section: Pathophysiology Of Lp(a)-induced Avsmentioning

confidence: 99%

Lipoprotein(a) as Orchestrator of Calcific Aortic Valve Stenosis

et al. 2019

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“…Most of these biological processes and pathways enriched in the BD gene signature overlap with those responsible for the development of atherosclerosis [43,44]. This suggests that the association between BD and cardiovascular diseases may have some genetic basis rather than shared environmental risk factors or side effects of psychotropic medications.…”

Section: Discussionmentioning

confidence: 99%

Large-scale differential gene expression analysis identifies genes associated with Bipolar Disorder in post-mortem brain

Omar

Youssef

Abdel-Latif

2019

Preprint

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Background and purposeBipolar disorder (BD) is a common psychiatric disorder with high morbidity and mortality. Several polymorphisms have been found to be implicated in the pathogenesis of BD, however, these loci have small effect sizes that fail to explain the high heritability of the disease. Here, we provide more insights into the genetic basis of BD by identifying the differentially expressed genes (DEGs) and their associated pathways and biological processes in post-mortem brain tissues of patients with BD. MethodsEight datasets were eligible for the differential expression analysis. We used six datasets for the discovery of the gene signature and used the other two for independent validation. We performed the multi-cohort analysis by a random-effect model using R and MetaIntegrator package. ResultsThe initial analysis resulted in the identification of 126 DEGs (30 up-regulated and 94 downregulated). We refined this initial signature by a forward search process and resulted in the identification of 22 DEGs (6 up-regulated and 16 down-regulated). We validated the final gene signature in the independent datasets and resulted in an Area Under the ROC Curve (AUC) of 0.756 and 0.76, respectively. We performed gene set enrichment analysis (GSEA) which identified several biological processes and pathways related to BD including Ca transport, inflammation and DNA damage response. ConclusionOur findings support the previous findings that link BD pathogenesis to abnormalities in glial inflammation and calcium transport and also identify several other biological processes not previously reported to be associated with the development of the disease. Such findings will improve our understanding of the genetic basis underlying BD and may have future clinical implications. INTRODUCTIONBipolar disorder (BD) is a common psychiatric disorder characterized by alternating periods of depression and abnormally elevated mood associated with cognitive impairments and increased impulsivity [1,2,3]. The lifetime prevalence of Bipolar disorder is approximately 2.4% with average age of onset of 25 years [4].Aside from mental and cognitive impairments, BD is also associated with high cardiovascular morbidity and mortality [5,6,7]. This association was explained by the co-occurrence of risk factors or due to side effects of psychotropic medications [8].On the neuro-anatomical level, neuro-imaging studies link BD to abnormalities in various areas of the brain, especially the frontal, prefrontal and parietal cortices with cortical thinning and increased ventricular volume [9, 10].On the genetic level, twin studies showed that BD is a highly heritable disease with heritability 2 reaching up to 80% [11, 12]. The risk of getting the disease is 10-fold higher in the first degree relatives of those affected with BD compared to normal population. Although recent studies showed that several susceptibility loci with small effect sizes are associated with BD [13, 14], there is no much evidence supporting the role of specific genes in the pathogene...

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“…Atherosclerosis occurs secondary to endothelial dysfunction that permits the retention of oxidized low‐density lipoprotein (LDL) in subendothelial space, which then induces the infiltration of immune cells and production of chemokines in endothelial cells (Weber & Noels, ). Anti‐inflammatory pathway‐associated therapeutic approaches have been suggested to improve the prognosis of AS patients who have received an optimal standard of care (Li, Li, Li, & Zhou, ). Circulating oxidized LDL, which is associated with the inflammatory variables of AS, plays a major role in the development of AS (Li et al., ).…”

Section: Introductionmentioning

confidence: 99%

“…Anti‐inflammatory pathway‐associated therapeutic approaches have been suggested to improve the prognosis of AS patients who have received an optimal standard of care (Li, Li, Li, & Zhou, ). Circulating oxidized LDL, which is associated with the inflammatory variables of AS, plays a major role in the development of AS (Li et al., ). It was also suggested that the judicious use of biomarkers and genetic information would reduce the risk of AS (Libby, Bornfeldt, & Tall, ).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA‐424‐5p regulates aortic smooth muscle cell function in atherosclerosis by blocking APOC3‐mediated nuclear factor‐κB signalling pathway

Zhang

Dai

et al. 2020

Experimental Physiology

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Dysregulated aortic smooth muscle cells in chronic inflammation result in plaque formation in atherosclerosis (AS), which is a systemic disease that affects the large arteries with the activation of inflammatory pathways as a key process in its pathogenesis. The aim of the study was to investigate the regulatory mechanism of microRNA-424-5p (miR-424-5p) in aortic smooth muscle cell activities and inflammation in AS via the regulation of apolipoprotein C3 (APOC3) and the nuclear factor-B (NF-B) signalling pathway. The results showed that miR-424-5p was poorly expressed and APOC3 highly expressed in the peripheral blood of AS patients and rat models of AS. Molecularly, our results confirmed that miR-424-5p targeted the APOC3 gene directly and inhibited APOC3 expression, which resulted in repressed activation of the NF-B signalling pathway. The gain-and loss-of-function approaches were used to determine the effects of miR-424-5p and APOC3 on inflammation and on the proliferation, apoptosis and migration of aortic smooth muscle cells. Upregulation of miR-424-5p or silencing of APOC3 significantly suppressed proliferation, migration and inflammation and promoted apoptosis of aortic smooth muscle cells, which was achieved through inactivation of the NF-B signalling pathway. Taken together, our results show that miR-424-5p upregulation impedes the progression of AS by blocking the APOC3-mediated NF-B signalling pathway, which could be used as a novel target and a potential therapeutic pathway against AS.

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Inflammation: A Novel Therapeutic Target/Direction in Atherosclerosis

Cited by 118 publications

References 188 publications

Lipoprotein(a) as Orchestrator of Calcific Aortic Valve Stenosis

Lipoprotein(a) as Orchestrator of Calcific Aortic Valve Stenosis

Large-scale differential gene expression analysis identifies genes associated with Bipolar Disorder in post-mortem brain

MicroRNA‐424‐5p regulates aortic smooth muscle cell function in atherosclerosis by blocking APOC3‐mediated nuclear factor‐κB signalling pathway

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