Metabolic Changes Induced by Bariatric Surgery May be Mediated by PAI-1 and PCSK9 Crosstalk.

BACKGROUND: Adiposity favors several metabolic disorders with an exacerbated chronic pro-inflammatory status and tissue damage, with high levels of plasminogen activator inhibitor type 1 (PAI-1) and proprotein convertase subtilisin/kexin type 9 (PCSK9). OBJECTIVE: To demonstrate the influence of bariatric surgery on the crosstalk between PAI-1 and PCSK9 to regulate metabolic markers. METHODS: Observational and longitudinal study of 190 patients with obesity and obesity-related comorbidities who underwent bariatric surgery. We measured, before and after bariatric surgery, the anthropometric variables and we performed biochemical analysis by standard methods (glucose, insulin, triglycerides [TG], total cholesterol, high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C] and TG/HDL-C ratio, PAI-1 and PCSK9 were measured by ELISA). RESULTS: PAI-1 levels decreased significantly after bariatric surgery, and were positively correlated with lipids, glucose, and TG, with significance on PCSK9 and TG/HDL-C alleviating the insulin resistance (IR) and inducing a state reversal of type 2 diabetes (T2D) with a significant decrease in body weight and BMI (p <0.0001). Multivariate regression analysis predicted a functional model in which PAI-1 acts as a regulator of PCSK9 (p <0.002), TG (p <0.05), and BMI; at the same time, PCSK9 modulates LDL-C HDL-C and PAI-1. CONCLUSIONS: After bariatric surgery, we found a positive association and crosstalk between PAI-1 and PCSK9, which modulates the delicate balance of cholesterol, favoring the decrease of circulating lipids, TG, and PAI-1, which influences the glucose levels with amelioration of IR and T2D, demonstrating the crosstalk between fibrinolysis and lipid metabolism, the two main factors involved in atherosclerosis and cardiovascular disease in human obesity.

Genome-Wide Association of Proprotein Convertase Subtilisin/Kexin Type 9 Plasma Levels in the ELSA-Brasil Study.

Pharmacological inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9) is an established therapeutic option to treat hypercholesterolemia, and plasma PCSK9 levels have been implicated in cardiovascular disease incidence. A number of genetic variants within the PCSK9 gene locus have been shown to modulate PCSK9 levels, but these only explain a very small percentage of the overall PCSK9 interindividual variation. Here we present data on the genetic association structure between PCSK9 levels and genom-wide genetic variation in a healthy sample from the general population. We performed a genome-wide association study of plasma PCSK9 levels in a sample of Brazilian individuals enrolled in the Estudo Longitudinal de Saude do Adulto cohort (n=810). Enrolled individuals were free from cardiovascular disease, diabetes and were not under lipid-lowering medication. Genome-wide genotyping was conducted using the Axiom_PMRA.r3 array, and imputation was performed using the TOPMED multi-ancestry sample panel as reference. Total PCSK9 plasma concentrations were determined using the Quantikine SPC900 ELISA kit. We observed two genome-wide significant loci and seven loci that reached the pre-defined value of p threshold of 1×10-6. Significant variants were near KCNA5 and KCNA1, and LINC00353. Genetic variation at the PCSK9 locus was able to explain approximately 4% of the overall interindividual variations in PCSK9 levels. Colocalization analysis using eQTL data suggested RWDD3, ATXN7L1, KCNA1, and FAM177A1 to be potential mediators of some of the observed associations. Our results suggest that PCSK9 levels may be modulated by trans genetic variation outside of the PCSK9 gene and this may have clinical implications. Understanding both environmental and genetic predictors of PCSK9 levels may help identify new targets for cardiovascular disease treatment and contribute to a better assessment of the benefits of long-term PCSK9 inhibition.

Variants of PCSK9 Gene Are Associated with Subclinical Atherosclerosis and Cardiometabolic Parameters in Mexicans. The GEA Project.

BACKGROUND: Coronary artery disease (CAD) is a chronic, inflammatory, and complex disease associated with vascular risk factors. Nowadays, the coronary artery calcium (CAC) is a specific marker of the presence and extent of atherosclerosis. Additionally, CAC is a predictor of future coronary events in asymptomatic individuals diagnosed with subclinical atherosclerosis (CAC > 0). In this study, our aim is to evaluate the participation of two polymorphisms of the PCSK9 gene as genetic markers for developing subclinical atherosclerosis and cardiometabolic risk factors in asymptomatic individuals. METHODS: We analyzed two PCSK9 polymorphisms (rs2479409 and rs615563) in 394 individuals with subclinical atherosclerosis and 1102 healthy controls using real time- polymerase chain reaction (PCR). RESULTS: Under various inheritance models adjusted for different confounding factors, the rs2479409 polymorphism was associated with an increased risk of developing subclinical atherosclerosis (OR = 1.53, P recessive = 0.041). Both polymorphisms were significantly associated with several cardiometabolic parameters. CONCLUSIONS: Our data suggest that rs2479409 polymorphism could be envisaged as a risk marker for subclinical atherosclerosis.

New Perspectives on Atherogenic Dyslipidaemia and Cardiovascular Disease.

Over the past few decades, atherogenic dyslipidaemia has become one of the most common phenotypic presentations of lipid abnormalities, being strongly and unequivocally associated with an increased risk of cardiovascular (CV) disease. Despite the excellent results achieved from statin and non-statin management of LDL cholesterol and CV events prevention, there still remains a significant residual risk, associated with the prevalence of non-LDL cholesterol lipid patterns characterised by elevated triglyceride levels, low HDL cholesterol, a preponderance of small and dense LDL particles, accumulation of remnant lipoproteins and postprandial hyperlipidaemia. These qualitative and quantitative lipid modifications are largely associated with insulin resistance, type 2 diabetes and obesity, the prevalence of which has grown to epidemic proportions throughout the world. In this review, we analyse the pathophysiology of this particular dyslipidaemia, its relationship with the development of atherosclerotic CV disease and, finally, briefly describe the therapeutic approaches, including changes in lifestyle and current pharmacological interventions to manage these lipid alterations aimed at preventing CV events.

Characterization of LDLR rs5925 and PCSK9 rs505151 genetic variants frequencies in healthy subjects from northern Chile: Influence on plasma lipid levels.

BACKGROUND: Identification and characterization of genetic variants and their effects on human health may allow to establish relationships between genetic background and susceptibility to developing cardiovascular diseases. LDLR and PCSK9 polymorphisms have been associated with higher lipid levels and risk of cardiovascular diseases. Thus, the main aim of this study was to evaluate genotype distribution and relative allelic frequency of LDLR rs5925 (1959C > T) and PCSK9 rs505151 (23968 A > G) genetic variants and their effects on lipid levels of healthy subjects from northern Chile. METHODS: A total of 178 healthy individuals were recruited for this study. The genotyping of rs5925 (LDLR) and rs505151 (PCSK9) polymorphisms was performed by PCR-RFLP and qPCR, respectively. In addition, glucose and lipid levels were determined and associated with the genetic data. RESULTS: Genotype distribution for LDLR rs5925 polymorphism was as follows: CC = 19%; CT = 53%; and TT = 28% (HWE: χ2  = 0.80; P = .37), and for PCSK9 rs505151 genetic variant was as follows: AA = 93%; AG = 7%; and GG = 0% (HWE: χ2  = 0.22; P = .64). The frequency of T (rs5925) and G (rs505151) mutated alleles was 0.55 and 0.03, respectively. Data showed that individuals carrying LDLR mutated allele (T) presented lower values of total cholesterol, triglycerides, and LDL-cholesterol when compared to CC homozygous genotype (P < .05). Subgroup analysis revealed that women carrying the PCSK9 mutated allele (G) exhibited higher values of total cholesterol, triglycerides, HDL-C, and LDL-C when compared to male group carrying the same genotype (P < .05). CONCLUSIONS: The effect of LDLR rs5925 and PCSK9 rs505151 gene polymorphisms on lipid levels is associated with gender among healthy subjects from northern Chile.

PCSK9 inhibitors in the current management of atherosclerosis / Los inhibidores de la PCSK9 en el manejo clínico actualizado de la aterosclerosis

Abstract: The history of proprotein convertase subtilisin/kexin type 9 (PCSK9) in medical science is fascinating and the evolution of knowledge of its function has resulted in new medications of major importance for the cardiovascular (CV) patient. PCSK9 functions as a negative control or feedback for the cell surface receptors for low-density lipoprotein including its component of cholesterol (LDL-C). The initial and key findings were that different abnormalities of PCSK9 can result in an increase or a decrease of LDL-C because of more or less suppression of cell surface receptors. These observations gave hints and awoke interest that it might be possible to prepare monoclonal antibodies to PCSK9 and decrease its activity, after which there should be more active LDL-C cell receptors. The rest is a fascinating story that currently has resulted in two PCSK9 inhibitors, alirocumab and evolocumab, which, on average, decrease LDL-C approximately 50%. Nevertheless, if there are no contraindications, statins remain the standard of prevention for the high-risk CV patient and this includes both secondary and primary prevention. The new inhibitors are for the patient that does not attain the desired target for LDL-C reduction while taking a maximum statin dose or who does not tolerate any statin dose whatsoever. Atherosclerosis can be considered a metabolic disease and the clinician needs to realize this and think more and more of CV prevention. These inhibitors can contribute to both the stabilization and regression of atherosclerotic plaques and thereby avoid or delay major adverse cardiac events. (United States)

Resumen: La historia de la proproteína convertasa subtilisin/kexin tipo 9 (PCSK9) es fascinante y la evolución del conocimiento de su función ha resultado en nuevos fármacos de gran importancia para el paciente cardiovascular. La PCSK9 funciona como un control negativo de receptores en la superficie de células para la lipoproteína de baja densidad con su componente de colesterol (LDL-C). El hallazgo inicial y clave fue que anormalidades diferentes de la PCSK9 resultan en un aumento o una disminución de la LDL-C, relacionados en una mayor o menor supresión de los receptores. Fueron estas observaciones las que proporcionaron evidencias indirectas a la idea de preparar anticuerpos monoclonales de la PCSK9 que pudieran disminuir su actividad y que esto se reflejara en receptores más activos para disminuir la LDL-C. El resto es una historia fascinante que ahora ofrece 2 inhibidores de la PCSK9, alirocumab y evolocumab, los cuales disminuyen la LDL-C en un 50%. Sin embargo, si no hay una contraindicación, las estatinas son el estándar de prevención para el paciente cardiovascular de alto riesgo e incluyen la prevención secundaria y primaria. Estos nuevos inhibidores están indicados en aquel paciente en el que no se obtiene el objetivo de tratamiento con la dosis máxima de una estatina o que no tolera ninguna de ellas. Debemos pensar en la aterosclerosis como una enfermedad metabólica y el clínico necesita darse cuenta de esta realidad y considerar las posibilidades disponibles para la prevención cardiovascular. Estos inhibidores pueden contribuir a la estabilización y regresión de placas ateroscleróticas y evitar episodios cardiovasculares mayores. (Estados Unidos)

PCSK9 inhibitors in the current management of atherosclerosis.

The history of proprotein convertase subtilisin/kexin type 9 (PCSK9) in medical science is fascinating and the evolution of knowledge of its function has resulted in new medications of major importance for the cardiovascular (CV) patient. PCSK9 functions as a negative control or feedback for the cell surface receptors for low-density lipoprotein including its component of cholesterol (LDL-C). The initial and key findings were that different abnormalities of PCSK9 can result in an increase or a decrease of LDL-C because of more or less suppression of cell surface receptors. These observations gave hints and awoke interest that it might be possible to prepare monoclonal antibodies to PCSK9 and decrease its activity, after which there should be more active LDL-C cell receptors. The rest is a fascinating story that currently has resulted in two PCSK9 inhibitors, alirocumab and evolocumab, which, on average, decrease LDL-C approximately 50%. Nevertheless, if there are no contraindications, statins remain the standard of prevention for the high-risk CV patient and this includes both secondary and primary prevention. The new inhibitors are for the patient that does not attain the desired target for LDL-C reduction while taking a maximum statin dose or who does not tolerate any statin dose whatsoever. Atherosclerosis can be considered a metabolic disease and the clinician needs to realize this and think more and more of CV prevention. These inhibitors can contribute to both the stabilization and regression of atherosclerotic plaques and thereby avoid or delay major adverse cardiac events. (United States).

Influence of PCSK9 polymorphisms on plasma lipids and response to atorvastatin treatment in Brazilian subjects.

BACKGROUND: The proprotein convertase subtilisin/kexin type 9 (PCSK9) has a key role in the regulation of plasma low-density lipoprotein (LDL) cholesterol by enhancing the degradation of LDL receptor. Functional variants in PCSK9 have been associated with differences in plasma lipids and may contribute to the variability of the response to cholesterol-lowering drugs. OBJECTIVE: To investigate the influence of PCSK9 variants on plasma lipid profile and response to atorvastatin in Brazilian subjects. METHODS: PCSK9 E670G, I474V, and R46L single nucleotide polymorphisms (SNPs) and plasma lipids were evaluated in 163 hypercholesterolemics (HC) and 171 normolipidemics (NL). HC patients with indication for cholesterol-lowering drug therapy (n = 128) were treated with atorvastatin (10 mg/d/4 wk). PCSK9 SNPs were analyzed by real time polymerase chain reaction. RESULTS: Frequencies of the PCSK9 SNPs were similar between the HC and NL groups. Logistic regression analysis showed a trend of association between PCSK9 E670G and hypercholesterolemia after adjustment for covariates (P = .059). The 670G allele was associated with high basal levels of LDL cholesterol (P = .03) in HC patients using the extreme discordant phenotype method. No association tests were performed for R46L variant because of its very low frequency, whereas the I474V polymorphism and PCSK9 haplotypes were not related to hypercholesterolemia or variability on plasma lipids in both NL and HC groups (P > .05). LDL cholesterol reduction in response to atorvastatin was not influenced by PCSK9 genotypes or haplotypes. CONCLUSIONS: PCSK9 E670G polymorphism but not I474V contributes to the variability on plasma LDL cholesterol levels in hypercholesterolemic subjects. Both PCSK9 variants have no influence on cholesterol-lowering response to atorvastatin.