Pharmarcogenetic Mechanism of ACE I/D Polymorphism Adversely Responding to ACE Inhibitors in Regulating the ACE Promoter Activity in Neurons

Abstract

Abstract:The ACE (angiotensin converting enzyme) inhibitors are not only drugs widely prescribed drugs in cardiovascular diseases, but also potentially therapeutic agents in dementia. Based on the findings that the ACE inhibitors could activate the c-Jun N-terminal kinase signal to increase the ACE gene expression and that the Alu element of the human ACE gene involved in regulating ACE promoter activity, we aimed to investigate whether there are different pharmacogenetic responses of ACE I/D polymorphism to the ACE inhibitors in neurons. The three reporter vectors, pACEpro(f)-SEAP, p-I-ACEpro-SEAP, and p-D-ACEpro-SEAP were used to examine the transcriptional activity of the vectors responding to the lisinopril treatment using a transient-transfection method in SH-SY5Y cells. Our results showed that lisinopril increased the promoter activity of an ACE gene by 16.7%. Additionally, we found the lisinopril enhanced the ACE promoter activity of the I-form vector by 17.2%, but adversely reduced that of the D-form vector by 16.8%, as compared with the respective control without the lisinopril treatment. Firstly, our findings had proved that the I/D polymorphism of ACE gene contrarily responds to the ACE inhibitors in regulating the ACE expression in neurons, which provide a novel insight suggesting genetic testing to tailor the treatment regimens in AD (Alzheimer's disease) patients.

ACE inhibitor, captopril, attenuates cytopathic effects of herpes simplex virus 1 in SH-SY5Y cells

“…Thus, the concentration needed to reduce HSV-1 replication is well below its active range in inhibiting ACE. Other RAAS inhibitors, such as losartan, have been evaluated in vivo for antiviral effects using a concentration of 12mg/kg 17,18 against coxsackievirus B3 which induces myocarditis. Des-aspartate-angiotensin I, an angiotensin nonapeptide, has also been shown to have an antiviral effect against rhinovirus when used between a 10 -10 and 10 -12 nanomolar range 10 .…”