scholarly journals WWP1 Deficiency Alleviates Cardiac Remodeling Induced by Simulated Microgravity

2021 ◽  
Vol 9 ◽  
Author(s):  
Guohui Zhong ◽  
Dingsheng Zhao ◽  
Jianwei Li ◽  
Zifan Liu ◽  
Junjie Pan ◽  
...  
Keyword(s):  
Cardiac Remodeling ◽  
Simulated Microgravity ◽  
Histological Analysis ◽  
Pressure Overload ◽  
Tail Suspension ◽  
Calcium Calmodulin Dependent ◽  
Segment Polarity ◽  
Histone Deacetylase 4 ◽  
Dependent Protein ◽  
And Function

Cardiac muscle is extremely sensitive to changes in loading conditions; the microgravity during space flight can cause cardiac remodeling and function decline. At present, the mechanism of microgravity-induced cardiac remodeling remains to be revealed. WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) is an important activator of pressure overload-induced cardiac remodeling by stabilizing disheveled segment polarity proteins 2 (DVL2) and activating the calcium-calmodulin-dependent protein kinase II (CaMKII)/histone deacetylase 4 (HDAC4)/myocyte-specific enhancer factor 2C (MEF2C) axis. However, the role of WWP1 in cardiac remodeling induced by microgravity is unknown. The purpose of this study was to determine whether WWP1 was also involved in the regulation of cardiac remodeling caused by microgravity. Firstly, we detected the expression of WWP1 and DVL2 in the heart from mice and monkeys after simulated microgravity using western blotting and immunohistochemistry. Secondly, WWP1 knockout (KO) and wild-type (WT) mice were subjected to tail suspension (TS) to simulate microgravity effect. We assessed the cardiac remodeling in morphology and function through a histological analysis and echocardiography. Finally, we detected the phosphorylation levels of CaMKII and HDAC4 in the hearts from WT and WWP1 KO mice after TS. The results revealed the increased expression of WWP1 and DVL2 in the hearts both from mice and monkeys after simulated microgravity. WWP1 deficiency alleviated simulated microgravity-induced cardiac atrophy and function decline. The histological analysis demonstrated WWP1 KO inhibited the decreases in the size of individual cardiomyocytes of mice after tail suspension. WWP1 KO can inhibit the activation of the DVL2/CaMKII/HDAC4 pathway in the hearts of mice induced by simulated microgravity. These results demonstrated WWP1 as a potential therapeutic target for cardiac remodeling and function decline induced by simulated microgravity.

scholarly journals WWP1 deficiency protects from cardiac remodeling induced by simulated microgravity

2021 ◽  
Author(s):  
Guohui Zhong ◽  
Dingsheng Zhao ◽  
Jianwei Li ◽  
Zifan Liu ◽  
Junjie Pan ◽  
...  
Keyword(s):  
Cardiac Remodeling ◽  
Simulated Microgravity ◽  
Histological Analysis ◽  
Pressure Overload ◽  
Hindlimb Unloading ◽  
Ubiquitin Protein Ligase ◽  
Cardiac Atrophy ◽  
Segment Polarity ◽  
And Function

Cardiac muscle is extremely sensitive to changes in loading conditions, the microgravity during space flight can cause cardiac remodeling and function decline. At present, the mechanism of microgravity-induced cardiac remodeling remains to be revealed. WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) is an important activator of pressure-overload induced cardiac remodeling by stabilizing disheveled segment polarity proteins 2 (DVL2) and activating CaMKII/HDAC4/MEF2C axis. However, the role of WWP1 in the cardiac remodeling induced by microgravity is unknown. The purpose of this study was to determine whether WWP1 was also involved in the regulation of cardiac remodeling caused by microgravity. Firstly, we detected the expression of WWP1 and DVL2 in the heart from mice and monkeys after simulated microgravity using western blotting and Immunohistochemistry. Secondly, WWP1 knockout (KO) and wild type mice were subjected to hindlimb unloading (HU) to simulate microgravity effect. We assessed the cardiac remodeling in morphology and function through histological analysis and echocardiography. Finally, we detected the phosphorylation level of CaMKII and HDAC4 in the heart from WT and WWP1 KO mice after HU. The results revealed the increased expression of WWP1 and DVL2 in the heart both from mice and monkey after simulated microgravity. WWP1 deficiency protected against simulated microgravity-induced cardiac atrophy and function decline. Histological analysis demonstrated WWP1 KO inhibited the decreases in the size of individual cardiomyocytes of mice after hindlimb unloading. WWP1 KO can inhibit the activation of DVL2/CaMKII/HDAC4 pathway in heart of mice induced by simulated microgravity. These results demonstrated WWP1 as a potential therapeutic target for cardiac remodeling and function decline induced by simulated microgravity. Keywords: WWP1, simulated microgravity, cardiac remodeling, DVL2, HDAC4.

scholarly journals KN-93, an inhibitor of calcium/calmodulin-dependent protein kinase IV, promotes generation and function of Foxp3+regulatory T cells in MRL/lprmice

Autoimmunity ◽  
2014 ◽  
Vol 47 (7) ◽  
pp. 445-450 ◽  
Author(s):  
Tomohiro Koga ◽  
Masayuki Mizui ◽  
Nobuya Yoshida ◽  
Kotaro Otomo ◽  
Linda A. Lieberman ◽  
...  
Keyword(s):  
T Cells ◽  
Protein Kinase ◽  
Regulatory T Cells ◽  
Dependent Protein Kinase ◽  
Calcium Calmodulin Dependent ◽  
Dependent Protein ◽  
And Function

scholarly journals CASK modulates the assembly and function of the Mint1/Munc18-1 complex to regulate insulin secretion

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Zhe Zhang ◽  
Wei Li ◽  
Guang Yang ◽  
Xuefeng Lu ◽  
Xin Qi ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Complex Formation ◽  
Ternary Complex ◽  
Β Cells ◽  
Serine Kinase ◽  
Interaction Sites ◽  
Calcium Calmodulin Dependent ◽  
Signaling Axis ◽  
Dependent Protein ◽  
And Function

AbstractCalcium/calmodulin-dependent protein serine kinase (CASK) is a key player in vesicle transport and release in neurons. However, its precise role, particularly in nonneuronal systems, is incompletely understood. We report that CASK functions as an important regulator of insulin secretion. CASK depletion in mouse islets/β cells substantially reduces insulin secretion and vesicle docking/fusion. CASK forms a ternary complex with Mint1 and Munc18-1, and this event is regulated by glucose stimulation in β cells. The crystal structure of the CASK/Mint1 complex demonstrates that Mint1 exhibits a unique “whip”-like structure that wraps tightly around the CASK-CaMK domain, which contains dual hydrophobic interaction sites. When triggered by CASK binding, Mint1 modulates the assembly of the complex. Further investigation revealed that CASK-Mint1 binding is critical for ternary complex formation, thereby controlling Munc18-1 membrane localization and insulin secretion. Our work illustrates the distinctive molecular basis underlying CASK/Mint1/Munc18-1 complex formation and reveals the importance of the CASK-Mint1-Munc18 signaling axis in insulin secretion.

Abstract 187: Identification of Cardiac-specific Downstream Substrates of Protein Kinase G I as Potential Novel Anti Cardiac Remodeling Targets

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Robert M Blanton ◽  
Angela Lane ◽  
Mark Aronovitz ◽  
Guang-rong Wang ◽  
Robrecht Thoonen ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cardiac Remodeling ◽  
Leucine Zipper ◽  
Pressure Overload ◽  
Protein Kinase G ◽  
Arterial Blood ◽  
293 Cells ◽  
Dependent Protein ◽  
Co Precipitation

We recently reported that mutation of the cGMP-dependent Protein Kinase G I alpha (PKGIα) N-terminal leucine zipper (LZ) domain (in the PKGIα LZ mutant, or LZM, mouse) accelerates LV remodeling and heart failure after TAC, and prevents the anti-remodeling effect of sildenafil. We therefore hypothesized that PKGIα attenuates remodeling by regulating cardiac signaling pathways that are dependent on substrate interactions mediated by its LZ domain. As a first step to identifying cardiac proteins downstream of PKGIα, we screened myocardial lysates for PKGIα LZ domain-interacting proteins. Our previous work revealed a requirement for the PKGIα LZ domain for the activation of anti-remodeling myocardial JNK activity after LV pressure overload. MLK3 is an MAPKKK that contains an LZ domain and activates JNK. We now demonstrate, by immunoprecipitation, that MLK 3 interacts with the PKGIα LZ domain in myocardial lysates. We show further that 8-Br-cGMP induces MLK3 phosphorylation on Threonine 277 and Serine 281 in WT, but not LZM myocardial lysates. And, in 293 cells transfected with FLAG-MLK3, 8Br-cGMP induced PKGIα-MLK3 co-precipitation, and increased phosphorylation of MLK3 on Thr277/Ser281. Co-transfection of MLK3 and PKGIα also induced MLK3 phosphorylation at the same sites. We next examined the cardiovascular effect of MLK3 deletion in vivo. Male 8 week old MLK3 -/- mice display basal bi-ventricular hypertrophy compared with littermate controls (LV/Tibia length 42.8 + 0.6 mg/cm in WT, 52.9 + 1.8 in MLK3 -/-; P <0.01; RV/TL 10.8 + 0.1 mg/cm in WT, 13.3 + 0.3 in MLK3 -/-; P <0.01; n= 7 WT, 5 MLK3 -/-). By 14-16 weeks of age, LVH progressed in the MLK3 -/- mice (LV/TL 47.7 + 1.3 mg/cm in WT, 59.8 + 7.5 in MLK3-/-; n= 6 WT, 9 MLK3-.-; P <0.01). Arterial blood pressure was modestly increased, though still normal, in the MLK3 -/- mice (SBP 93 + 1 in WT, 113 + 1 in MLK3 -/-). And, 14-16 week MLK3 -/- mice have impaired LV diastolic function (tau 3.2 + 0.1 ms WT, 3.7 + 0.1 MLK3-/-; P 0.06). Our studies reveal a previously unknown function of MLK3 as a myocardial PKGIα effector and inhibitor of LVH. Together these results support the strategy of exploring LZ-dependent PKGIα substrates in the myocardium to identify novel therapeutic targets for cardiac remodeling.

Sign in / Sign up

Export Citation Format

Share Document