This study aimed to detect the association between the MLX interacting protein-like (MLXIPL), BUD13 homolog (BUD13) and zinc finger protein 259 (ZNF259) single nucleotide polymorphisms (SNPs) and serum lipid levels in the Chinese Mulao and Han populations. Genotyping of 9 SNPs was performed in 825 Mulao and 781 Han participants. The genotype and allele frequencies of ZNF259 rs2075290 and rs964184, and BUD13 rs10790162 SNPs were different between the Mulao and Han populations (P < 0.001). The SNPs of ZNF259 rs2075290 and BUD13 rs10790162 were associated with serum total cholesterol levels; ZNF259 rs2075290 and rs964184, BUD13 rs10790162, and MLXIPL rs3812316 and rs13235543 were associated with triglyceride (TG); and MLXIPL rs35332062 was associated with apolipoprotein (Apo) A1 in the Mulaos (P < 0.006–0.001). However, in the Hans, the SNPs of ZNF259 rs2075290 and BUD13 rs10790162 were associated with serum TG levels; ZNF259 rs2075290 was associated with low-density lipoprotein cholesterol and the ApoA1/ApoB ratio (P < 0.006–0.001). Significant linkage disequilibria were noted among ZNF259 rs2075290 and rs964184 and BUD13 rs10790162, and between MLXIPL rs3812316 and rs13235543 (r2 > 0.05, P < 0.001). The haplotypes of A-C-G-A-C (rs2075290A-rs964184C-rs10790162G-rs17119975A-rs11556024C) and C-C-C-C (rs799161C-rs35332062C-rs3812316C-rs13235543C) accounted for over half of the % haplotype of each ethnic group.
Introduction: With the rapid development of sequencing technologies, several long non-coding RNAs (lncRNAs) have been identified; among which many are significant players in cardiac physiology and pathology. Doxorubicin (Dox), a commonly used anticancer agent, in the long-term can induce cardiotoxicity, limiting its clinical use. Despite the multiple signaling pathways involved in Dox cardiotoxicity, most of them ultimately lead to the activation of apoptosis, contributing to the progressive cardiomyocyte loss, and hence ensuring heart failure. Methods and Results: Microarray analysis showed that multiple lncRNAs were differentially expressed between control and doxorubicin-treated groups, denoting that lncRNAs may play a critical role in Dox cardiotoxicity. Functional enrichment analysis displayed that the differentially expressed genes are annotated to MAPK signaling and cardiac hypertrophic pathways. CMDL-1 is first characterized in rat cardiomyocytes and is the most significantly downregulated lncRNA after doxorubicin exposure. CMDL-1 is located upstream to the transient receptor potential cation channel, subfamily M, member 7 (Trpm-7), which can function as a kinase by phosphorylating itself or other substrates. Mechanistic analysis indicated that lentiviral overexpression of CMDL-1 decreased Dox-induced mitochondrial fission (MitoTracker Red CMXRos) and apoptosis (TUNEL and flow cytometry) in cardiomyocytes. Bioinformatic and experimental data showed that CMDL-1 could bind to Drp1. Overexpression of CMDL-1 promoted its association with Drp1, as well as with phosphorylated (p)-Drp1, evidenced by RNA immunoprecipitation analysis. However, overexpression of CMDL-1 couldn’t effectively reduce mitochondrial fission if Drp1 was minimally expressed by siDrp1. These findings suggest that CMDL-1 could prevent mitochondrial fission and apoptosis by impairing Drp1 phosphorylation. Conclusions: Collectively, we demonstrated that a novel lncRNA CMDL-1 could play a protective role in cardiac injury and could be a potential therapeutic target in Dox cardiotoxicity. Our study is additional evidence of the less appreciated mechanism of lncRNAs, modulating the phosphorylation status of its interacting proteins.
Background: ADAM 10 & 17, the two most well-known members of disintegrin and metalloproteinases (ADAMs), are responsible for the cleavage of diverse transmembrane proteins into bioactive molecules in the renal tubular cells. Objective: The purpose of this study is to understand the effects of ADAM 10 & 17 double-knockout (DKO) on renal and vascular functions using the renal tubular cell-specific ADAM 10 & 17 DKO mice. Results: We tested the renal and vascular functions in three groups (n=10-15 per group) of male and female wild-type (WT), vehicle, and DKO mice. The urine output ( P < 0.05) and glomerular filtration rate ( P < 0.01) of DKO mice were significantly lower than those of WT and vehicle control groups. The urinary sodium ( P < 0.0001) and potassium ( P < 0.01) excretion in DKO mice were also significantly reduced. Consistently, we found a significant decrease in urea ( P < 0.0001) and creatinine ( P < 0.0001) clearance in DKO mice, suggesting that the renal function is impaired when both ADAM 10 & 17 are depleted. In addition, the pulse wave velocity ( P < 0.0001), and blood pressure including systolic blood pressure ( P -value < 0.0001), diastolic blood pressure ( P < 0.0001), and mean blood pressure ( P < 0.0001) levels of DKO mice were significantly higher than those of WT and vehicle controls, indicating that ADAM 10 & 17 depletion impairs renal and vascular functions and causes hypertension. This phenomenon is further supported by the evidence that DKO mice showed a slower relaxation response to acetylcholine, compared to WTs. Next, to understand the changes in proteomic profiles in DKO kidneys, we performed proteomic analysis of WT and DKO kidney tissues and identified ~100 differentially expressed proteins (DEPs). These DEPs are highly enriched in drug metabolism, metabolic pathways, and TGF-beta signaling, PPAR-signaling and AGE-RAGE signaling pathways, suggesting that ADAM 10 & 17 may play a role in renal cellular metabolism, cell growth, differentiation, and apoptosis. Conclusions: The depletion of ADAM 10 & 17 impairs the renal and vascular functions likely via disrupting the cellular metabolism and homeostasis.
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