Pop1 Inhibits Pathological Cardiac Hypertrophy Through Geft

Myocardial hypertrophy is a stress response to stress and capacity overload in the heart.It is a complex pathophysiological process mediated by a variety of neurohumoral factors,in which various cell signaling pathways and gene expression are involved in regulation.Pathological hypertrophy often shows decreased contractilityassociated with arrhythmia,which eventually leading to heart failure and sudden death.Cardiac dysfunction reflects the different pathogenesis of pathological cardiac hypertrophy.The mechanism of intracellular hypertrophy signaling is not very clear.In this paper,1(Pop1)and p63 Rho GEF(Geft),two genes Popeye domains associated with pathologic cardiac hypertrophy were studied about their association in pathological hypertrophy.Previous studies have studied the role of Pop1 and Geft in pathological hypertrophy.Pop1,a gene encodes a large number of expressed plasma membrane-targeted c AMP binding proteins in striated muscle.In animal models,Pop1 is an important regulator of the structure and the function of heart and skeletal muscle.Geft also known as ARHGEF25,belongs to the Rho guanine nucleotide exchange factor(GEF)family.It is a membrane anchored protein.It is highly expressed in excitable tissues such as brain,heart and muscle.Geft knockout mice showed normal heart performance,but Geft knockout mice were more susceptible to pathological cardiac hypertrophy under ISO stimulation.The results above shows that Geft is an endogenous cardiomyocyte hypertrophy inhibitory factor.In this study,mice with Pop1 overexpression and Geft knockout were constructed and the model of myocardial hypertrophy was constructed under the stimulation of isoproterenol(ISO).We have twogroups through injecting saline(Sham)and ISO respectively.The heart and body weight ratio(HW / BW)and cardiac tibial length ratio(HW /TL)analysis showed that only Pop1 transgenic mice(TG)were inhibited in the ISO group.However,Pop1 overexpress group(TG +KO),subtracted the inhibition of cardiac hypertrophy induced by case stimulation in the context of the specific removal of Geft in the heart,showed excessive cardiac hypertrophy.The condition is similar to that of the Geft gene knockout mice.Western blot analysis showed that P-AKT,P-P38 and P-ERK were up-regulated under hypertrophic stimulation,and the activity was inhibited in Pop1 transgenic mice.The same inhibition could be reversed by Geft knockout,manifested as over-activation of Geft alone knockout.This suggests that Geft mediates the inhibitory effect of Pop1 on cardiac hypertrophy and its associated signaling pathways.To further validate the interrelationship between Pop1 and Geft in pathologic hypertrophy.We used the hypertrophy marker gene fluorescent reporter system NFAT-LUC and ANF-LUC to evaluate the synergistic effect of H9C2 rat cardiomyocytes.It was found that Pop1 and Geft could synergistically inhibit the fluorescence activity of both.And this synergy can be specifically eliminated by the Cdc42 inhibitor.These results suggest that Pop1 and Geft synergistically inhibit hypertrophy-related signaling through CDC42 through to resist the occurrence of pathological cardiac hypertrophy.