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Untypical Metabolic Adaptations in Spontaneously Hypertensive Rats to Free Running Wheel Activity Includes Uncoupling Protein-3 (UCP-3) and Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Expression.

ABSTRACT: Obesity and hypertension are common risk factors for cardiovascular disease whereas an active lifestyle is considered as protective. However, the interaction between high physical activity and hypertension is less clear. Therefore, this study investigates the impact of high physical activity on the muscular and hepatic expression of glucose transporters (Glut), uncoupling proteins (UCPs), and proprotein convertase subtilisin/kexin type 9 (PCSK9) in spontaneously hypertensive rats (SHRs). Twenty-four female rats (12 normotensive rats and 12 SHRs) were divided into a sedentary control and an exercising group that had free access to running wheels at night for 10 months. Blood samples were taken and blood pressure was determined. The amount of visceral fat was semi-quantitatively analyzed and Musculus gastrocnemius, Musculus soleus, and the liver were excised. Acute effects of free running wheel activity were analyzed in 15 female SHRs that were sacrificed after 2 days of free running wheel activity. M. gastrocnemius and M. soleus differed in their mRNA expression of UCP-2, UCP-3, GLUT-4, and PCSK9. Hypertension was associated with lower levels of UCP-2 and PCSK9 mRNA in the M. gastrocnemius, but increased expression of GLUT-1 and GLUT-4 in the M. soleus. Exercise down-regulated UCP-3 in the M. soleus in both strains, in the M. gastrocnemius only in normotensives. In SHRs exercise downregulated the expression of UCP-2 in the M. soleus. Exercise increased the expression of GLUT-1 in the M. gastrocnemius in both strains, and that of GLUT-4 protein in the M. soleus, whereas it increased the muscle-specific expression of PCSK9 only in normotensive rats. Effects of exercise on the hepatic expression of cholesterol transporters were seen only in SHRs. As an acute response to exercise increased expressions of the myokine IL-6 and that of GLUT-1 were found in the muscles. This study, based on transcriptional adaptations in striated muscles and livers, shows that rats perform long-term metabolic adaptations when kept with increased physical activity. These adaptations are at least in part required to stabilize normal protein expression as protein turnover seems to be modified by exercise. However, normotensive and hypertensive rats differed in their responsiveness. Based on these results, a direct translation from normotensive to hypertensive rats is not possible. As genetic differences between normotensive humans and patients with essential hypertension are likely to be present as well, we would expect similar differences in humans that may impact recommendations for non-pharmacological interventions.

SUBMITTER: Wolf A

PROVIDER: S-EPMC8021776 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundActivated macrophages contribute to the pathogenesis of vascular disease. Vein graft failure is a major clinical problem with limited therapeutic options. PCSK9 (proprotein convertase subtilisin/kexin 9) increases low-density lipoprotein (LDL)-cholesterol levels via LDL receptor (LDLR) degradation. The role of PCSK9 in macrophage activation and vein graft failure is largely unknown, especially through LDLR-independent mechanisms. This study aimed to explore a novel mechanism of macrophage activation and vein graft disease induced by circulating PCSK9 in an LDLR-independent fashion.MethodsWe used Ldlr-/- mice to examine the LDLR-independent roles of circulating PCSK9 in experimental vein grafts. Adeno-associated virus (AAV) vector encoding a gain-of-function mutant of PCSK9 (rAAV8/D377Y-mPCSK9) induced hepatic PCSK9 overproduction. To explore novel inflammatory targets of PCSK9, we used systems biology in Ldlr-/- mouse macrophages.ResultsIn Ldlr-/- mice, AAV-PCSK9 increased circulating PCSK9, but did not change serum cholesterol and triglyceride levels. AAV-PCSK9 promoted vein graft lesion development when compared with control AAV. In vivo molecular imaging revealed that AAV-PCSK9 increased macrophage accumulation and matrix metalloproteinase activity associated with decreased fibrillar collagen, a molecular determinant of atherosclerotic plaque stability. AAV-PCSK9 induced mRNA expression of the pro-inflammatory mediators IL-1β (interleukin-1 beta), TNFα (tumor necrosis factor alpha), and MCP-1 (monocyte chemoattractant protein-1) in peritoneal macrophages underpinned by an in vitro analysis of Ldlr-/- mouse macrophages stimulated with endotoxin-free recombinant PCSK9. A combination of unbiased global transcriptomics and new network-based hyperedge entanglement prediction analysis identified the NF-κB (nuclear factor-kappa B) signaling molecules, lectin-like oxidized LOX-1 (LDL receptor-1), and SDC4 (syndecan-4) as potential PCSK9 targets mediating pro-inflammatory responses in macrophages.ConclusionsCirculating PCSK9 induces macrophage activation and vein graft lesion development via LDLR-independent mechanisms. PCSK9 may be a potential target for pharmacologic treatment for this unmet medical need.

Project description:BACKGROUND:Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a hepatic enzyme that regulates circulating low-density lipoprotein (LDL) cholesterol levels by binding to LDL receptors (LDLR) and promoting their degradation. Although PCSK9 inhibitors were shown to reduce the risk of cardiovascular disease, a warning was issued concerning their possible impact on cognitive functions. In Alzheimer's disease (AD), it is believed that cognitive impairment is associated with cholesterol metabolism alterations, which could involve PCSK9. The main objective of this study is to determine if PCSK9 plays a significant role in the pre-symptomatic phase of the disease when the pathophysiological markers of AD unfolds and, later, when cognitive symptoms emerge. METHODS AND FINDINGS:To test if PCSK9 is associated with AD pathology, we measured its expression levels in 65 autopsy confirmed AD brains and 45 age and gender matched controls. Messenger ribonucleic acid (mRNA) were quantified using real-time polymerase chain reaction (RT-PCR) and protein levels were quantified using enzyme-linked immunosorbent assay (ELISA). PCSK9 was elevated in frontal cortices of AD subjects compared to controls, both at the mRNA and protein levels. LDLR protein levels were unchanged in AD frontal cortices, despite and upregulation at the mRNA level. To verify if PCSK9 dysregulation was observable before the onset of AD, we measured its expression in the cerebrospinal fluid (CSF) of 104 "at-risk" subjects and contrasted it with known apolipoproteins levels and specific AD biomarkers using ELISAs. Positive correlations were found between CSF PCSK9 and apolipoprotein E (APOE), apolipoprotein J (APOJ or CLU), apolipoprotein B (APOB), phospho Tau (pTau) and total Tau. To investigate if PCSK9 levels were driven by genetic variants, we conducted an expression quantitative trait loci (eQTL) study using bioinformatic tools and found two polymorphisms in strong association. Further investigation of these variants in two independent cohorts showed a female specific association with AD risk and with CSF Tau levels in cognitively impaired individuals. CONCLUSIONS:PCSK9 levels differ between control and AD brains and its protein levels correlate with those of other lipoproteins and AD biomarkers even before the onset of the disease. PCSK9 regulation seems to be under tight genetic control in females only, with specific variants that could predispose to increased AD risk.

Project description:BackgroundThe relationship between cholesterol levels and risk of venous thromboembolism (VTE) is uncertain. We set out to determine the effect of PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition on the risk of VTE, explore potential mechanisms, and examine the efficacy in subgroups with clinically and genetically defined risk.MethodsWe performed a post hoc analysis of the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) testing whether evolocumab reduces the risk of VTE events (deep venous thrombosis or pulmonary embolism). Data from FOURIER and ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment with Alirocumab) were then combined in a meta-analysis to assess the class effect of PCSK9 inhibition on the risk of VTE. We also analyzed baseline lipids in FOURIER to investigate potential mechanisms explaining the reduction in VTE with evolocumab. Last, an exploratory genetic analysis was performed in FOURIER to determine whether a VTE polygenic risk score could identify high-risk patients who would derive the greatest VTE reduction from evolocumab.ResultsIn FOURIER, the hazard ratio (HR) for VTE with evolocumab was 0.71 (95% CI, 0.50-1.00; P=0.05), with no effect in the 1st year (HR, 0.96 [95% CI, 0.57-1.62]) but a 46% reduction (HR, 0.54 [95% CI, 0.33-0.88]; P=0.014) beyond 1 year. A meta-analysis of FOURIER and ODYSSEY OUTCOMES demonstrated a 31% relative risk reduction in VTE with PCSK9 inhibition (HR, 0.69 [95% CI, 0.53-0.90]; P=0.007). There was no relation between baseline low-density lipoprotein cholesterol levels and magnitude of VTE risk reduction. In contrast, in patients with higher baseline lipoprotein(a) (Lp[a]) levels, evolocumab reduced Lp(a) by 33 nmol/L and risk of VTE by 48% (HR, 0.52 [95% CI, 0.30-0.89]; P=0.017), whereas, in patients with lower baseline Lp(a) levels, evolocumab reduced Lp(a) by only 7 nmol/L and had no effect on VTE risk (Pinteraction 0.087 for HR; Pheterogeneity 0.037 for absolute risk reduction). Modeled as a continuous variable, there was a significant interaction between baseline Lp(a) concentration and magnitude of VTE risk reduction (Pinteraction=0.04). A polygenic risk score identified patients who were at >2-fold increased risk for VTE and who derived greater relative (Pinteraction=0.04) and absolute VTE reduction (Pheterogeneity=0.009) in comparison with those without high genetic risk.ConclusionsPCSK9 inhibition significantly reduces the risk of VTE. Lp(a) reduction may be an important mediator of this effect, a finding of particular interest given the ongoing development of potent Lp(a) inhibitors.

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Untypical Metabolic Adaptations in Spontaneously Hypertensive Rats to Free Running Wheel Activity Includes Uncoupling Protein-3 (UCP-3) and Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Expression.

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