Synergistic Role of Protein Phosphatase Inhibitor 1 and SERCA2a in the Acquisition of the Contractile Phenotype of Arterial Smooth Muscle Cells
Background—Phenotypic modulation or switching of Vascular Smooth Muscle Cells (VSMC) from contractile/quiescent to a proliferative/synthetic phenotype plays a key role in vascular proliferative disorders, such as atherosclerosis and restenosis. Although several calcium handling proteins that control differentiation of SMCs have been identified, the role of protein phosphatase inhibitor 1 (I-1) in the acquisition and/or maintenance of the contractile phenotype modulation remain unknown.
Methods and Results—In human coronary arteries, I-1 and Sarco/endoplasmic Reticulum Ca2+-ATPase (SERCA2a) expression is specific to contractile VSMCs. In synthetic cultured human coronary artery SMC (hCASMCs), protein phosphatase inhibitor 1 (PP1; I-1 target) is highly expressed, leading to a decrease in Phospholamban (PLB) phosphorylation, SERCA2 and cAMP Responsive Element Binding (CREB) activity. I-1 knock-out mice lack PLB phosphorylation and exhibit VSMC arrest in the synthetic state with excessive neointimal proliferation following carotid injury, and significant modifications of contractile properties and relaxant response to acetylcholine (ACh) of femoral artery in vivo. Constitutively active I-1 (I-1c) gene transfer decreased neointimal formation in an angioplasty rat model by preventing VSMC contractile to synthetic phenotype change
Conclusions—I-1 and SERCA2a synergistically induce the VSMC contractile phenotype. Gene transfer of I-1c is a promising therapeutic strategy for preventing vascular proliferative disorders.
- Calcium Cycling
- Protein Phosphatase Inhibitor 1
- vascular disease
- muscle, smooth
- gene therapy
- Received March 12, 2013.
- Revision received October 31, 2013.
- Accepted November 8, 2013.