Dominant role of CACNA1D exon mutations for blood pressure regulation.

BACKGROUND: CACNA1D gene, which encodes the α1 subunit of the Cav1.3 L-type calcium channel effectively regulates intracellular Ca2+ stability. In recent years, clinical studies have shown that the CACNA1D polymorphisms were associated with hypertension. OBJECTIVE: The purpose of this study was to evaluate the effects of CACNA1D exon mutation on blood pressure (BP) in Sprague-Dawley rats. METHODS: The rats with CACNA1D p.D307G, CACNA1D p.V936I or CACNA1D p.R1516Q were constructed using CRISPR-Cas9 technology. SBP measurements of rats were taken for 32 weeks. Tissue morphology of rats and vasoactive substances in serum was tested. Furthermore, the effects of L-type calcium channel blocker isradipine and endothelin-1 (ET-1) inhibitor BQ-123 on BP of double mutation rats (CACNA1D p.D307G/p.R1516Q) were tested. Then we examined the effects of CACNA1D gene mutation on gene expression in human umbilical vein endothelial cells (HUVECs) and vascular smooth muscle cells (VSMCs). RESULTS: Elevated SBP and increased circulating ET-1 was observed in CACNA1D p.D307G mutant rats. Morphological assessments showed that the vascular, cardiac and renal remodeling could also be observed in rats with p.D307G mutant. Cav1.3 protein expression and calcineurin phosphatase activity in VSMCs of rats with CACNA1D p.D307G were increased in vitro, and the vascular ring tension test of mesenteric grade 3 arteries in CACNA1D p.D307G rats were increased in vivo. Furthermore, ET-1 expression were increased in isolated primary aortic endothelial cells in p.D307G mutant rats and transfected p.D307G mutant HUVECs. Finally, double heterozygosity rats with CACNA1D p.D307G/p.R1516Q or CACNA1D p.D307G/p.V936I further accelerated the rise of SBP compared with p.D307G mutation rats, and isradipine and BQ-123 reduced BP to the same extent in CACNA1D p.D307G/p.R1516Q rats. CONCLUSION: CACNA1D gene is key players in the regulation of blood pressure. CACNA1D mutation rat may be a new hypertension animal model.

APOE polymorphism is associated with blood lipid and serum uric acid metabolism in hypertension or coronary heart disease in a Chinese population.

Aim: To explore the association of APOE polymorphism (rs7412:526C>T and rs429358:388T>C) with glucose, lipid and serum uric acid (UA) metabolism in patients with hypertension or coronary heart disease (CHD). Methods: A total of 544 patients with hypertension or CHD were selected for this study from March 2017 to January 2018. According to the APOE genotypes (excluding the E2/E4 genotype), the subjects were divided into three groups (E2/E2+E2/E3 genotypes, E3/E3 genotype [the wild-type] and E3/E4+E4/E4 genotypes) and the difference of metabolism among the three groups was compared. Results: There were significant differences in total cholesterol (TC), triglycerides, low-density lipoprotein (LDL), high-density lipoprotein and serum UA levels among the three groups. Compared with APOE E3 homozygote, APOE E4 carriers possessed higher TC, triglycerides and LDL levels, whereas APOE E2 carriers had higher high-density lipoprotein level, lower TC and LDL levels. Furthermore, multivariate logistic regression analysis found that setting E3/E3 genotype as the reference group, the carriers of APOE E4 allele (E3/E4+E4/E4 genotypes) were significantly related to hypertriglyceridemia, and APOE E2 allele (E2/E2+E2/E3 genotypes) was significantly correlated with hyperuricemia. Conclusion:APOE polymorphism was associated with blood lipid and serum UA metabolism in patients with hypertension or CHD. Compared with APOE E3 homozygote, APOE E4 allele was related to elevated triglycerides, and APOE E2 allele was correlated with increased serum UA level.