PKG and SRF, Important Regulatory Factors Involved with Vascular Smooth Muscle Gene Expression

Abstract

Vascular smooth muscle cell (VSMC) gene expression is altered in vascular diseases such as atherosclerosis. The NO/cGMP pathway appears to prevent the fibro‐proliferative response of VSMC in such instances. Cyclic GMP‐dependent protein kinase (PKG), the down‐stream mediator of NO/cGMP signaling, has been shown to regulate VSMC phenotype and stimulate VSMC gene expression. Serum response factor (SRF), a transcription factor associated with many signaling pathways including smooth muscle‐specific gene expression stimulates VSMC gene expression. The key objective of this study was to determine if PKG regulates SRF expression or translocation into the nucleus in VSMC. Results obtained: Primary cultures of VSMC were used to test whether PKG‐I activity increases SRF expression or translocation in VSMC. Down regulation of endogenous PKG‐I using siRNA decreased PKG‐I expression, but did not affect the overall level of SRF expression in VSMC. Over‐expression of PKG‐I caused increased SRF to be translocated to the nucleus, coincident with increased expression of smooth muscle myosin heavy chain. These effects were reversed in VSMC over‐expressing PKG‐I along with siRNA treatment. Conclusion: Up‐regulation of PKG‐I expression in VSMC may increase VSMC specific gene expression by increasing the SRF level in the nuclear compartment.Supported by NIH grants: 5T32HL076125 and RO1HL53426