The First Defense Of Cardiac Hypertrophy

It is well known that cardiomyocytes accompany fetal type transition in the process of hypertrophic growth. However, nobody theoretically deciphers cell type transitions as the cause in occurence and development of diseases. In the past, much effort was focused on the fetal gene reprogram in cardiac hypertrophy, which was considered to be the direct etiology factor. But how they are reactivated needs to be elucidated.It is well known that a set of genes that function as cardiac protector are reactivated in the adult heart in response to pathologic stimuli, However,little is known about the genes reduced in cardiac hypertrophy that function primarily in normal adult heart maintenance.In response to hypertrophic stimulis, there are at least two group endogenous negative molecules in cardiomyocytes. One group of these molecules reduced under the stimulation condition is constitutively active at baseline, while molecules belonging to the second group serve as negative feedback regulators, which are activated in response to pathologic insults. We hypothesis the fetal gene reprogram partly be derived from decrease the first group molecules in the cardiac hypertrophy. Loss of the defense of such first group factors may be the primary cause to cardiac hypertrophy. In this regard, the genes reduced in response to hypertrophic stimulis would play important roles in occerence of heart disease. Especially, the fisrt group of negative regulators might function as the supervisor preventing from cardiac pathological transition under the pathologic insults. So they constitute the first defense in heart hypertrophic growth. To this end, we perform a systemic research about the molecular member decrease in the cardiac hypertrophy at different levels of signaling pathway transduction including membrane protein,membrane anchoring protein and cytoplasmic protein.Pop1 is a membrane protein which abundant in heart and skeletal muscle. Here, we showed that overexpression of Popl in vitro inhibited the hypertrophic cell growth caused by PE agonists treatment. Popl cardiomyocyte-specific transgenic mice could ameliorate the cardiac hypertrophy induced by isoproterenol treatment with downregulation of P-Akt. In this study, we identify Pop1 as a novel cardiac protective molecule. Its downregulation would be deleterious for heart homeostasis.Pop1 as a membrane protein might wander between different receptors and play an important role in the signaling transmitting by mediating the cross talk of different signaling pathway. Our study provides in vivo genetic evidence to show the function of Pop 1.Geft is a guanine nucleotide exchange factor, which can specifically activate Rho family of small GTPase by catalyzing the exchange of bound GDP for GTP. Geft is highly expressed in heart and skeletal muscle. It is previously reported that interaction with Pop1 and regulation of speed of cell locomotion and cell roundness. Here, we found cardiac specific knock out Geft showed more susceptivity under isoproterenol stimulation, along with increase of P-Akt. In this study, we identify Geft as a novel endogenous cardiac protective molecule. The decrease of Geft might lead to release the inhibition to enlarge responsiveness to hypertrophic stimulis. Our data provides the first in vivo genetic evidence to show the function Geft.In the cytoplasm, hypertrophic stimulis ultimately lead to fetal gene reprogram. There are also negative factors at the end-point of cardiac hypertrophy. Lrrc10 is specific abundant in heart. We found overexpression of LrrclO in primary cardiac myocytes attenuated the hypertrophic cell growth caused by treatment with hypertrophic agonists and cardiac-specific Lrrc10 transgenic mice revealed that Lrrc10 overexpression could ameliorate the cardiac hypertrophy induced by isoproterenol treatment. Further study showed that Lrrc10 interacted with SRF to inhibit it's transactivation by redistributing it from the nucleus to the cytoplasm. Thus, our study indicated doweregulation of Lrrc10 released SRF and increased heart susceptivity in response to hypertrophic stimuli. Conversely, in the normal condition, SRF seemed to be enjailed by abundant factors to avoid heart's pathological transition. In the sense,Lrrc10 seemed function as a supervisor of SRF in cardiac hypertrophy. It might be one reason for re-employment of developmental factors in adult heart disease.In conclusion, our systemic study indicated the in vivo roles of Geft,Pop1 and Lrrc10 in adult heart. Our data demonstrated that the first group endogenous negative regulators widely existed in full process of signaling pathway. The inactivation of these factor in heart lead to fetal gene reprogram and increase the responsiveness in response to hypertrophic stimulis, then supported that the first group of negative regulators might constitute the first defense of cardiac hypertrophy. Our study suggested a new clue for clinic heart disease prevention and therapy, provided a new clue for clinic heart disease prevention and therapyIn addition, we identified Rmnd5a as a novel member of TGF-?signaling pathway, validated that Rmnd5a interacted with Smad7 and influenced TGF-? signaling pathway related to cell biology and cardiac hypertrophy. Our study identify Rmnd5a as a novel TGF-? signaling pathway negative regulator, mostly likely function as an inhibitor of tumour metastasis and inducer of cardiac hypertrophy. We coloned and analyzed the different length of Lrrc10 promoter, indicated that GATA4 and MEF2C could both increase transcriptional activity of Lrrc10 promoter individually but that they did not act synergistically, the likely GATA4 binding site identified was located in a region only 100 base pair(bp) upstream of the promoter. Our data provided insight into the molecular regulation of Lrrc10 expression, which probably also contributes to its tissue-specific expression.