The role of cAMP/PKA signaling enhancer Protein Phosphatase Inhibitor 1 (I‐1) in the control of Ca2+ cycling and signaling in VSMCs

Abstract

The Ca2+ cycling in “contractile” vascular smooth muscle cells (VSMC) requires the expression of SERCA2a, whereas in “proliferating” ones is associated with the expression of SERCA2b only. Inhibitor‐1 (I‐1), a highly specific inhibitor of protein phosphatase 1 (PP1), enhances both PKA‐dependent Phospholamban (PLB) phosphorylation and SERCA activity.The goal of this study was to elucidate the role of I‐1 in the control of VSMC Ca2+ cycling. In humans and rodents, the expression of I‐1 was found to be specific for contractile VSMC, whereas PP1 was highly expressed in synthetic VSMC. Genetic deletion of I‐1 in mice model resulted in lack of PLB phosphorylation in VSMC. Despite the fact that SERCA2a was expressed, VSMCs from I‐1 deficient mice were locked in the proliferating state, with the development of a vascular proliferative disorder and excessive neointimal proliferation after vascular injury. Gene transfer of constitutively active I‐1 (I‐1c) significantly increased PLB phosphorylation and Ca2+ uptake in both synthetic and contractile VSMCs. Therefore, I‐1c prevented proliferation and remodeling of contractile VSMC, but had no effect on synthetic VSMC, which predominantly express SERCA2b.In conclusion, Gene transfer of I‐1c may be considered as a promising therapeutic strategy for preventing vascular proliferative diseases.