Interaction of Angiotensinogen and Angiotensin-converting Enzyme Gene Polymorphisms in Predicting Essential Hypertension: a haplotype analysis

本研究目的在於探討血管張力素 元、張力素轉化與第一型張力素受器 基因之haplotype 是否與本態性高血壓 有關。方法：共有408 位病人與286 位 正常人鑑定上述三種基因之多態型。利 用permutation 為基礎的假設分析三種 基因haplotypes 與高血壓之關連，並分 析個別基因之互相作用。結果發現血管 張力素元基因之haplotype 與高血壓有 關。而此種關連只見餘於張力素轉化 基因為II 型者。因此高血壓之關連研 究，有基因之間的互相作用存在。There are many reports demonstrating the association of renin-angiotensin system gene polymorphisms with hypertension in different populations. In the present study, we used haplotype analyses of the angiotensinogen gene with a new permutation-based hypothesis testing method to determine the association between multilocus angiotensinogen gene polymorphisms and hypertension in a relatively homogeneous Taiwanese population. We also genotyped angiotensin converting enzyme gene insertion/ deletion polymorphism and angiotensin II type I receptor gene A1166C polymorphism to detect epistatic gene-gene interactions. There were 408 patients with hypertension (hypertensives) and 286 controls. The angiotensinogen gene haplotype frequencies were significantly different between hypertensives and controls, and this finding was only present in subjects with angiotensin converting enzyme gene II genotypes when the analysis was stratified by genotype of this polymorphism. In addition, the angiotensinogen gene hyplotype structure of hypertensives was more heterogeneous than that of controls. Our results showed that angiotensinogen gene haplotypes were associated with hypertension, and might play a synergistic action with I allele of angiotensin converting enzyme gene

Protein Kinase C-Fyn Kinase Cascade Mediates the Oleic Acid-Induced Disassembly of Neonatal Rat Cardiomyocyte Adherens Junctions

Oleic acid (OA) affects assembly of gap junctions in neonatal cardiomyocytes. Adherens junction (AJ) regulates the stability of gap junction integrity; however, the effect of OA on AJ remains largely unexplored. The distribution of N-cadherin and catenins at cell-cell junction was decreased by OA. OA induced activation of protein kinase C( PKC)-alpha and -epsilon and Src family kinase, and all three kinases were involved in the oleic acid-induced disassembly of the adherens junction, since it was blocked by pretreatment with Go6976 (a PKC alpha inhibitor), epsilon VI-2 (a PKC epsilon inhibitor), or PP2 (a Src family kinase inhibitor). Src family kinase appeared to be the downstream of PKC-alpha and -epsilon, as blockade of either PKC-alpha or -epsilon activity prevented the OA-induced activation of Src family kinase. Immunoprecipitation analyses showed that CIA activated Fyn and Fer. OA promoted the association of p120 catenin/beta-catenin with Fyn and Ferand caused increased tyrosine phosphorylation of p120 catenin and beta P- catenin, resulting in decreased binding of the former to N-cadherin and of the latter to alpha-catenin. Pretreatment with PP2 abrogated this OA- induced tyrosine phosphorylation of p120 catenin and beta-catenin and restored the association of N- cadherin with p120 catenin and that of beta -catenin with alpha-catenin. In conclusion, these results show that CA activates the PKC-Fyn signaling pathway, leading to the disassembly of the AJ. Therefore. inhibitors of PKC-alpha/- epsilon and Src family kinase are potential candidates as cardioprotection agents against OA-induced heart injury during ischemia-reperfusion