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Apolipoprotein C-III and cardiovascular diseases: when genetics meet molecular pathologies.

ABSTRACT: Cardiovascular diseases (CVD) have overtaken infectious diseases and are currently the world's top killer. A quite strong linkage between this type of ailments and elevated plasma levels of triglycerides (TG) has been always noticed. Notably, this risk factor is mired in deep confusion, since its role in atherosclerosis is uncertain. One of the explanations that aim to decipher this persistent enigma was provided by apolipoprotein C-III (apoC-III), a small protein historically recognized as an important regulator of TG metabolism. Preeminently, hundreds of studies have been carried out in order to explore the APOC3 genetic background, as well as to establish a correlation between its variants and dyslipidemia-related disorders, pointing to an earnest predictive power for future outcomes. Among several polymorphisms reported within the APOC3, the SstI site in its 3'-untranslated region (3'-UTR) was the most consistently and robustly associated with an increased CVD risk. As more genetic data supporting its importance in cardiovascular events aggregate, it was declared, correspondingly, that apoC-III exerts various atherogenic effects, either by intervening in the function and catabolism of many lipoproteins, or by inducing endothelial inflammation and smooth muscle cells (SMC) proliferation. This review was designed to shed the light on the structural and functional aspects of the APOC3 gene, the existing association between its SstI polymorphism and CVD, and the specific molecular mechanisms that underlie apoC-III pathological implications. In addition, the translation of all these gathered knowledges into preventive and therapeutic benefits will be detailed too.

SUBMITTER: Dib I

PROVIDER: S-EPMC7778846 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Apolipoprotein C-III and cardiovascular diseases: when genetics meet molecular pathologies.

Dib Israa I Khalil Alia A Chouaib Racha R El-Makhour Yolla Y Noureddine Hiba H

Molecular biology reports 20210103 1

Cardiovascular diseases (CVD) have overtaken infectious diseases and are currently the world's top killer. A quite strong linkage between this type of ailments and elevated plasma levels of triglycerides (TG) has been always noticed. Notably, this risk factor is mired in deep confusion, since its role in atherosclerosis is uncertain. One of the explanations that aim to decipher this persistent enigma was provided by apolipoprotein C-III (apoC-III), a small protein historically recognized as an i ...[more]

PMID: 33389539

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Project description:Cardiovascular disease (CVD) is an evolving process that begins in the early stages of chronic kidney disease (CKD) in children. Several surrogate markers, such as ambulatory blood pressure monitoring (ABPM), left ventricular (LV) mass, and arterial stiffness assessment, allow for the early detection of subclinical CVD in pediatric CKD. Four groups of plasma samples (n = 3/group) from congenital anomalies of the kidney and urinary tract (CAKUT), as well as non-CAKUT patients with or without BP abnormalities, were studied to screen differentially expressed proteins using isobaric tags for relative and absolute protein quantification (iTRAQ)-based proteomics. As a result, 20 differentially expressed proteins associated with hypertension in children with CKD were discovered. Among them, apolipoprotein C-II (apoC-II) was found to have the highest abundance among the CKD patients with hypertension. As such, we hypothesized that apoC-II and apolipoprotein C-III (apoC-III) levels were related to BP abnormalities and CVD in children suffering from mild-to-moderate CKD. We examined their associations with surrogate markers of CV risk in 88 pediatric patients with CKD stages G1-G4. Children with CKD stages G2-G4 had a higher plasma apoC-II level than G1 patients (6.35 vs. 5.05 mg/dl, p < 0.05). We observed that ABPM abnormalities, LV mass, and arterial stiffness parameters were greater in CKD children who had stages G2-G4 than in those who had stage G1 (all p < 0.05). Plasma levels of apoC-II and apoC-III were positively correlated with total cholesterol, triglyceride, and low-density lipoprotein (LDL) (all p < 0.001). In multivariate linear regression analyses, apoC-II was correlated with a high LV mass index and an abnormal ABPM profile, and apoC-III was correlated with 24-h hypertension (r = 0.303, p = 0.003) and asleep hypertension (r = 0.379, p < 0.001). Early evaluations of apoC-II and apoC-III, ABPM, and surrogate markers of CV risk will aid in early preventative interventions to reduce the risk of CV in youths suffering from CKD.

Project description:Canonical WNT signaling through Frizzled and LRP5/6 receptors is transduced to the WNT/β-catenin and WNT/stabilization of proteins (STOP) signaling cascades to regulate cell fate and proliferation, whereas non-canonical WNT signaling through Frizzled or ROR receptors is transduced to the WNT/planar cell polarity (PCP), WNT/G protein-coupled receptor (GPCR) and WNT/receptor tyrosine kinase (RTK) signaling cascades to regulate cytoskeletal dynamics and directional cell movement. WNT/β-catenin signaling cascade crosstalks with RTK/SRK and GPCR-cAMP-PKA signaling cascades to regulate β-catenin phosphorylation and β-catenin-dependent transcription. Germline mutations in WNT signaling molecules cause hereditary colorectal cancer, bone diseases, exudative vitreoretinopathy, intellectual disability syndrome and PCP-related diseases. APC or CTNNB1 mutations in colorectal, endometrial and prostate cancers activate the WNT/β-catenin signaling cascade. RNF43, ZNRF3, RSPO2 or RSPO3 alterations in breast, colorectal, gastric, pancreatic and other cancers activate the WNT/β-catenin, WNT/STOP and other WNT signaling cascades. ROR1 upregulation in B-cell leukemia and solid tumors and ROR2 upregulation in melanoma induce invasion, metastasis and therapeutic resistance through Rho-ROCK, Rac-JNK, PI3K-AKT and YAP signaling activation. WNT signaling in cancer, stromal and immune cells dynamically orchestrate immune evasion and antitumor immunity in a cell context-dependent manner. Porcupine (PORCN), RSPO3, WNT2B, FZD5, FZD10, ROR1, tankyrase and β-catenin are targets of anti-WNT signaling therapy, and ETC-159, LGK974, OMP-18R5 (vantictumab), OMP-54F28 (ipafricept), OMP-131R10 (rosmantuzumab), PRI-724 and UC-961 (cirmtuzumab) are in clinical trials for cancer patients. Different classes of anti-WNT signaling therapeutics are necessary for the treatment of APC/CTNNB1-, RNF43/ZNRF3/RSPO2/RSPO3- and ROR1-types of human cancers. By contrast, Dickkopf-related protein 1 (DKK1), SOST and glycogen synthase kinase 3β (GSK3β) are targets of pro-WNT signaling therapy, and anti-DKK1 (BHQ880 and DKN-01) and anti-SOST (blosozumab, BPS804 and romosozumab) monoclonal antibodies are being tested in clinical trials for cancer patients and osteoporotic post-menopausal women. WNT-targeting therapeutics have also been applied as reagents for in vitro stem-cell processing in the field of regenerative medicine.

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Apolipoprotein C-III and cardiovascular diseases: when genetics meet molecular pathologies.

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Apolipoprotein C-III and cardiovascular diseases: when genetics meet molecular pathologies.

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