Protein Kinase GI Isoforms Differentially Regulate Vascular Smooth Muscle Cell Proliferation

Compounds that increase levels of cAMP and cGMP are beneficial in a variety of diseases, including pulmonary hypertension, erectile dysfunction, angina, and peripheral arterial occlusions, due in large part, to the ability of cyclic nucleotides to inhibit vascular smooth muscle cell (VSMC) growth. Most studies report that cGMP‐dependent protein kinase g (PKG) negatively regulates vascular proliferation, however a few publications have shown that PKGI promotes vascular remodeling and atherogenesis. We hypothesized that the two isoforms of PKGI oppose one another in regulating VSMC proliferation. We found that PKGIα localizes to the nucleus of synthetic VSMC, but is cytoplasmic in quiescent VSMC. However PKGIβ is found only in the cytoplasm of both synthetic and quiescent VSMC. Overexpression of a dominant‐negative form of PKGIα caused increased expression of p27, a cell cycle inhibitor. This was not observed when dominant‐negative PKGIβ was overexpressed. Furthermore, we found that PKGI (α & β) knockout cells grow more slowly than wild‐type cells. These data suggest that PKGIα promotes VSMC proliferation, while PKGIβ inhibits growth. Because PKGIα and Iβ display different subcellular locations and functions, specifically targeting these isoforms may attenuate the abnormal growth of VSMC associated with vascular diseases. This work is supported by a pre‐doctoral grant from the American Heart Association