Abstract 3753: ACE Inhibition Results in Transcriptional Regulation of the Contractile Phenotype of Vascular Smooth Muscle to Reverse Nitrate Tolerance in Congestive Heart Failure
Background - CHF is characterized by abnormal vasoconstriction and an impairment in nitric oxide (NO)-mediated vasodilatation. We have demonstrated that the decrease in sensitivity to NO lies at least partially at the level of the smooth muscle and is due to a reduction in the relative expression of the leucine zipper positive (LZ+) isoform of the myosin targeting subunit (MYPT1) of myosin light chain phosphatase. We hypothesized that since the attenuated vasodilatory response to NO in CHF has been shown to be secondary to an increased activity of the renin-angiotensin system, ACE inhibition maintains LZ+ MYPT1 isoform expression.
Methods and Results - To test this hypothesis, a rat MI model of CHF was used; following left coronary artery ligation, rats were divided into control and captopril treated groups. A third group of rats was given prazosin for 4 weeks. In the untreated control group, left ventricular function (LVF) was reduced at 2 weeks post-MI and remained at this level. Captopril treatment attenuated the fall in LVF. In the control aorta and iliac artery, the expression of the LZ+ MYPT1 isoform fell between 2– 4 weeks post-MI, whereas in animals treated with captopril, MYPT1 isoform expression did not change. A decrease in the sensitivity to cGMP mediated relaxation mirrored that of LZ+ MYPT1 expression. The change in LZ+ MYPT1 expression was not due to the decrease in afterload, as prazosin was as effective as captopril in preserving LVF but did not increase the relative expression of LZ+ MYPT1 isoform. Gene microarray analysis demonstrated that captopril treatment resulted in the differential expression of only 21 genes, including known transcriptional regulators.
Conclusions - These data suggest that ACE inhibition, unique from pure afterload reduction, prevents MYPT1 isoform switching via G-protein coupled receptor signaling and transcriptional regulation to preserve normal flow, or NO-mediated vasodilatation. This sheds new light on the possible mechanism of ACE inhibitors to prevent nitrate tolerance in long-term nitrate therapy.