The Study Of The Function And Molecular Mechanism Of Hippo Signal Transduction Pathway In Hypertrophic Cardiomyopathy

Objective: Hippo-MST signal transduction pathway has been confirmed that plays animportant role to control the size of several organs and the development of tumor, butwhether this pathway affects the occurrence and development of hypertrophiccardiomyopathy has not been reported. This study aimed to investigate the expressionof Hippo-MST signal transduction pathway in human hypertrophic myocardium ofhypertrophic cardiomyopathy and its regulation in occurrence of cardiac hypertrophy,what’s more to study more about the mechanism of hypertrophic cardiomyopathy.Methods: This study consists of three parts:1. Patients with hypertrophiccardiomyopathy:35cases of myocardial tissues from patients with hypertrophiccardiomyopathy who were received surgery to clear the left ventricular outflow tractfrom September2011to April2013in Beijing Anzhen Hospital and4cases of normalmyocardial tissues;2. Mouse model of cardiac-specific genetic abnormalities:Establishing two kinds of mouse models with specific Mst knockout (Mst-KO) orspecific transgenic Yap (TG) in heart of mouse;3. Mouse model with cardiachypertrophy induced by Isoproterenol (ISO)：Injecting respectively ISO into Mst-KO,TG and their littermate wild-type (WT) male mice to make hypertrophic cardiachypertrophy in mice. Study subjects were examined by echocardiography and theirventricular muscles were obtained. H&E staining showed the morphology ofventricular muscle cells, Western blotting and Real-time PCR were used to detect the expression of molecules related Hippo-MST signal transduction pathway in proteinand transcriptional levels, respectively.Results:1. Compared to the normal myocardium, Mst transcription levels in septalmyocardium of hypertrophic cardiomyopathy patients decreased significantly, aboutnearly50%(p <0.05), correspondingly, the expression of MST protein decreasedsignificantly about more than75%, meanwhile MST protein expression andpreoperative septal thickness were negatively correlated;2. Compared to the normalmyocardium, the activity of YAP protein in septal myocardium of hypertrophiccardiomyopathy patients was significantly higher, increased about more than twotimes, while the inactive form P-S127-YAP protein expression decreased nearly50%(p <0.05);.3. With the mouse age increased, we observed the enlarged heart size ofmice with Mst downregulation or Yap overexpression, cardiac mass index increasedsignificantly at28weeks after birth, about33%or25%(both p <0.05).4. Comparedwith the littermate wild-type (WT) mice treated without ISO, the myocardialhypertrophy were more serious in Mst-KO or TG mice receiving ISO.5. Comparedwith the littermate control group, MST protein expression of WT mice heart waslower in the ISO model and P-S127-YAP expression also reduced about70%(p <0.05). Compared with WT mice in the ISO model, P-S127-YAP expression ofMST-KO mice decreased more obviously, declined more than80%(p <0.05).6. InISO model, YAP protein expression of TG mice heart was significantly seven-foldhigher than that in wild-type mice, while the P-S127-YAP protein expression reducedsignificantly about more than90%(p <0.05).Conclusions: Hippo-MST signal transduction pathway may play certain role inregulating the occurrence of hypertrophic cardiomyopathy. Low expression of Mst or overexpression of Yap in Hippo-MST pathway could increase transcriptional activityof YAP and expression of some molecules related specific genes involved in theproliferation of myocardial cells, affect hypertrophy of myocardial tissue, and thusparticipate in the pathogenesis of hypertrophic cardiomyopathy.