The Effects Of Mutant ANP On Vascular Smooth Muscle Cells

Atrial natriuretic peptide(ANP) is a powerful vasodilator, and a protein(polypeptide)hormone secreted by heart muscle cells. It is involved in the homeostatic control of body water, sodium, potassium and fat. The binding of ANP to its receptor causes the conversion of GTP to cGMP and raises intracellular cGMP. As a consequence, cGMP activates a cGMP-dependent kinase(PKG) and its downstream pathways. Various effects of the ANP have been reported, including the effect on blood pressure, endothelium permeability, intravascular volume, cardiac hypertrophy and fibrosis, vascular relaxation and remodeling, and lipid metabolism.We have reported a ANP mutant, p.I134 T, genetically linked with lone atrial fibrillation in Chinese population. ANP receptors highly expressed in vascular smooth muscle cells(VSMCs). While treated by the mutant ANP(mANP), reduced vasodilation activity compared with wild ANP(wANP). VSMCs proliferation and phenotypic modulation were also changed by mANP. To elucidate the molecular mechanism of mANP effect in VSMCs,we analyzed expression of genes in the pathway of ANP/NPR-A/cGMP/PKG and ANP/NPR-C/cAMP/AKT(Ser473). Lowered cGMP pathway genes suggested that mANP negatively regulated NPR-A.To verify whether ANP also plays biological effects through NPR-C, we knockdown the expression of NPR-C by applying specific siRNA in VSMCs. The result displayed it can reduce the phosphorylation level of ERK and AKT(Ser473).Overall, these data indicate that the mANP affects VSMCs' function through NPR-A/cGMP/protein kinase G pathway and ANP/NPR-C/AKT pathway.