IU Indianapolis ScholarWorks :: Browsing by Author "Shou, Weinian"

Browsing by Author "Shou, Weinian"

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2017 Riley Heart Center Symposium on Cardiac Development: Development and Repair of the Ventricular Wall
(Springer Nature, 2018-08) Field, Loren J.; Shou, Weinian; Markham, Larry; Pediatrics, School of Medicine
Atrial fibrillation and electrophysiology in transgenic mice with cardiac-restricted overexpression of FKBP12
(American Physiological Society, 2019-02-01) Pan, Zhenwei; Ai, Tomohiko; Chang, Po-Cheng; Liu, Ying; Liu, Jijia; Maruyama, Mitsunori; Homsi, Mohamed; Fishbein, Michael C.; Rubart, Michael; Lin, Shien-Fong; Xiao, Deyong; Chen, Hanying; Chen, Peng-Sheng; Shou, Weinian; Li, Bai-Yan; Medicine, School of Medicine
Cardiomyocyte-restricted overexpression of FK506-binding protein 12 transgenic (αMyHC-FKBP12) mice develop spontaneous atrial fibrillation (AF). The aim of the present study is to explore the mechanisms underlying the occurrence of AF in αMyHC-FKBP12 mice. Spontaneous AF was documented by telemetry in vivo and Langendorff-perfused hearts of αMyHC-FKBP12 and littermate control mice in vitro. Atrial conduction velocity was evaluated by optical mapping. The patch-clamp technique was applied to determine the potentially altered electrophysiology in atrial myocytes. Channel protein expression levels were evaluated by Western blot analyses. Spontaneous AF was recorded in four of seven αMyHC-FKBP12 mice but in none of eight nontransgenic (NTG) controls. Atrial conduction velocity was significantly reduced in αMyHC-FKBP12 hearts compared with NTG hearts. Interestingly, the mean action potential duration at 50% but not 90% was significantly prolonged in αMyHC-FKBP12 atrial myocytes compared with their NTG counterparts. Consistent with decreased conduction velocity, average peak Na+ current ( INa) density was dramatically reduced and the INa inactivation curve was shifted by approximately +7 mV in αMyHC-FKBP12 atrial myocytes, whereas the activation and recovery curves were unaltered. The Nav1.5 expression level was significantly reduced in αMyHC-FKBP12 atria. Furthermore, we found increases in atrial Cav1.2 protein levels and peak L-type Ca2+ current density and increased levels of fibrosis in αMyHC-FKBP12 atria. In summary, cardiomyocyte-restricted overexpression of FKBP12 reduces the atrial Nav1.5 expression level and mean peak INa, which is associated with increased peak L-type Ca2+ current and interstitial fibrosis in atria. The combined electrophysiological and structural changes facilitated the development of local conduction block and altered action potential duration and spontaneous AF. NEW & NOTEWORTHY This study addresses a long-standing riddle regarding the role of FK506-binding protein 12 in cardiac physiology. The work provides further evidence that FK506-binding protein 12 is a critical component for regulating voltage-gated sodium current and in so doing has an important role in arrhythmogenic physiology, such as atrial fibrillation.
BMP10 preserves cardiac function through its dual activation of SMAD-mediated and STAT3-mediated pathways
(Elsevier, 2019-12-27) Qu, Xiuxia; Liu, Ying; Cao, Dayan; Chen, Jinghai; Liu, Zhuo; Ji, Hongrui; Chen, Yuwen; Zhang, Wenjun; Zhu, Ping; Xiao, Deyong; Li, Xiaohui; Shou, Weinian; Chen, Hanying; Pediatrics, School of Medicine
Bone morphogenetic protein 10 (BMP10) is a cardiac peptide growth factor belonging to the transforming growth factor β superfamily that critically controls cardiovascular development, growth, and maturation. It has been shown that BMP10 elicits its intracellular signaling through a receptor complex of activin receptor-like kinase 1 with morphogenetic protein receptor type II or activin receptor type 2A. Previously, we generated and characterized a transgenic mouse line expressing BMP10 from the α-myosin heavy chain gene promoter and found that these mice have normal cardiac hypertrophic responses to both physiological and pathological stimuli. In this study, we report that these transgenic mice exhibit significantly reduced levels of cardiomyocyte apoptosis and cardiac fibrosis in response to a prolonged administration of the β-adrenoreceptor agonist isoproterenol. We further confirmed this cardioprotective function with a newly generated conditional Bmp10 transgenic mouse line, in which Bmp10 was activated in adult hearts by tamoxifen. Moreover, the intraperitoneal administration of recombinant human BMP10 was found to effectively protect hearts from injury, suggesting potential therapeutic utility of using BMP10 to prevent heart failure. Gene profiling and biochemical analyses indicated that BMP10 activates the SMAD-mediated canonical pathway and, unexpectedly, also the signal transducer and activator of transcription 3 (STAT3)-mediated signaling pathway both in vivo and in vitro Additional findings further supported the notion that BMP10's cardioprotective function likely is due to its dual activation of SMAD- and STAT3-regulated signaling pathways, promoting cardiomyocyte survival and suppressing cardiac fibrosis.
Critical Roles of STAT3 in β-Adrenergic Functions in the Heart
(American Heart Association, 2016-01-05) Zhang, Wenjun; Qu, Xiuxia; Chen, Biyi; Snyder, Marylynn; Wang, Meijing; Li, Baiyan; Tang, Yue; Chen, Hanying; Zhu, Wuqiang; Zhan, Li; Yin, Ni; Li, Deqiang; Li, Xie; Liu, Ying; Zhang, J. Jillian; Fu, Xin-Yuan; Rubart, Michael; Song, Long-Sheng; Huang, Xin-Yun; Shou, Weinian; Department of Pediatrics, IU School of Medicine
BACKGROUND: β-Adrenergic receptors (βARs) play paradoxical roles in the heart. On one hand, βARs augment cardiac performance to fulfill the physiological demands, but on the other hand, prolonged activations of βARs exert deleterious effects that result in heart failure. The signal transducer and activator of transcription 3 (STAT3) plays a dynamic role in integrating multiple cytokine signaling pathways in a number of tissues. Altered activation of STAT3 has been observed in failing hearts in both human patients and animal models. Our objective is to determine the potential regulatory roles of STAT3 in cardiac βAR-mediated signaling and function. METHODS AND RESULTS: We observed that STAT3 can be directly activated in cardiomyocytes by β-adrenergic agonists. To follow up this finding, we analyzed βAR function in cardiomyocyte-restricted STAT3 knockouts and discovered that the conditional loss of STAT3 in cardiomyocytes markedly reduced the cardiac contractile response to acute βAR stimulation, and caused disengagement of calcium coupling and muscle contraction. Under chronic β-adrenergic stimulation, Stat3cKO hearts exhibited pronounced cardiomyocyte hypertrophy, cell death, and subsequent cardiac fibrosis. Biochemical and genetic data supported that Gαs and Src kinases are required for βAR-mediated activation of STAT3. Finally, we demonstrated that STAT3 transcriptionally regulates several key components of βAR pathway, including β1AR, protein kinase A, and T-type Ca(2+) channels. CONCLUSIONS: Our data demonstrate for the first time that STAT3 has a fundamental role in βAR signaling and functions in the heart. STAT3 serves as a critical transcriptional regulator for βAR-mediated cardiac stress adaption, pathological remodeling, and heart failure.
Dbh+ catecholaminergic cardiomyocytes contribute to the structure and function of the cardiac conduction system in murine heart
(Springer Nature, 2023-11-28) Sun, Tianyi; Grassam-Rowe, Alexander; Pu, Zhaoli; Li, Yangpeng; Ren, Huiying; An, Yanru; Guo, Xinyu; Hu, Wei; Liu, Ying; Zheng, Yuqing; Liu, Zhu; Kou, Kun; Ou, Xianhong; Chen, Tangting; Fan, Xuehui; Liu, Yangyang; Tu, Shu; He, Yu; Ren, Yue; Chen, Ao; Shang, Zhouchun; Xia, Zhidao; Miquerol, Lucile; Smart, Nicola; Zhang, Henggui; Tan, Xiaoqiu; Shou, Weinian; Lei, Ming; Pediatrics, School of Medicine
The heterogeneity of functional cardiomyocytes arises during heart development, which is essential to the complex and highly coordinated cardiac physiological function. Yet the biological and physiological identities and the origin of the specialized cardiomyocyte populations have not been fully comprehended. Here we report a previously unrecognised population of cardiomyocytes expressing Dbhgene encoding dopamine beta-hydroxylase in murine heart. We determined how these myocytes are distributed across the heart by utilising advanced single-cell and spatial transcriptomic analyses, genetic fate mapping and molecular imaging with computational reconstruction. We demonstrated that they form the key functional components of the cardiac conduction system by using optogenetic electrophysiology and conditional cardiomyocyte Dbh gene deletion models. We revealed their close relationship with sympathetic innervation during cardiac conduction system formation. Our study thus provides new insights into the development and heterogeneity of the mammalian cardiac conduction system by revealing a new cardiomyocyte population with potential catecholaminergic endocrine function.
Deletion of the glucocorticoid receptor chaperone FKBP51 prevents glucocorticoid-induced skin atrophy
(Impact Journals, 2018-10-05) Baida, Gleb; Bhalla, Pankaj; Yemelyanov, Alexander; Stechschulte, Lance A.; Shou, Weinian; Readhead, Ben; Dudley, Joel T.; Sánchez, Edwin R.; Budunova, Irina; Pediatrics, School of Medicine
FKBP51 (FK506-binding protein 51) is a known co-chaperone and regulator of the glucocorticoid receptor (GR), which usually attenuates its activity. FKBP51 is one of the major GR target genes in skin, but its role in clinical effects of glucocorticoids is not known. Here, we used FKBP51 knockout (KO) mice to determine FKBP51's role in the major adverse effect of topical glucocorticoids, skin atrophy. Unexpectedly, we found that all skin compartments (epidermis, dermis, dermal adipose and CD34+ stem cells) in FKBP51 KO animals were much more resistant to glucocorticoid-induced hypoplasia. Furthermore, despite the absence of inhibitory FKBP51, the basal level of expression and glucocorticoid activation of GR target genes were not increased in FKBP51 KO skin or CRISPR/Cas9-edited FKBP51 KO HaCaT human keratinocytes. FKBP51 is known to negatively regulate Akt and mTOR. We found a significant increase in AktSer473 and mTORSer2448 phosphorylation and downstream pro-growth signaling in FKBP51-deficient keratinocytes in vivo and in vitro. As Akt/mTOR-GR crosstalk is usually negative in skin, our results suggest that Akt/mTOR activation could be responsible for the lack of increased GR function and resistance of FKBP51 KO mice to the steroid-induced skin atrophy.
Dishevelled-associated activator of morphogenesis 1 (Daam1) is required for heart morphogenesis
(2011-01) Li, Deqiang; Hallett, Mark A.; Zhu, Wuqiang; Rubart, Michael; Liu, Ying; Yang, Zhenyun; Chen, Hanying; Haneline, Laura S.; Chan, Rebecca J.; Schwartz, Robert J.; Field, Loren J.; Atkinson, Simon J.; Shou, Weinian
Dishevelled-associated activator of morphogenesis 1 (Daam1), a member of the formin protein family, plays an important role in regulating the actin cytoskeleton via mediation of linear actin assembly. Previous functional studies of Daam1 in lower species suggest its essential role in Drosophila trachea formation and Xenopus gastrulation. However, its in vivo physiological function in mammalian systems is largely unknown. We have generated Daam1-deficient mice via gene-trap technology and found that Daam1 is highly expressed in developing murine organs, including the heart. Daam1-deficient mice exhibit embryonic and neonatal lethality and suffer multiple cardiac defects, including ventricular noncompaction, double outlet right ventricles and ventricular septal defects. In vivo genetic rescue experiments further confirm that the lethality of Daam1-deficient mice results from the inherent cardiac abnormalities. In-depth analyses have revealed that Daam1 is important for regulating filamentous actin assembly and organization, and consequently for cytoskeletal function in cardiomyocytes, which contributes to proper heart morphogenesis. Daam1 is also found to be important for proper cytoskeletal architecture and functionalities in embryonic fibroblasts. Biochemical analyses indicate that Daam1 does not regulate cytoskeletal organization through RhoA, Rac1 or Cdc42. Our study highlights a crucial role for Daam1 in regulating the actin cytoskeleton and tissue morphogenesis.
DISHEVELLED-ASSOCIATED ACTIVATOR OF MORPHOGENESIS 1 (DAAM1) IS REQUIRED FOR HEART MORPHOGENESIS
(2010-02-02T19:55:35Z) Li, Deqiang; Shou, Weinian; Field, Loren J.; Payne, R. Mark; Zhang, Xin
Dishevelled-associated activator of morphogenesis 1 (Daam1), a member of the formin protein family, has been implicated in the non-canonical Wnt mediated Planar Cell Polarity (PCP) signaling pathway. Although the studies in Drosophila Daam1 and Xenopus Daam1 generated inconsistent conclusions regarding the function of Daam1, the biological function of mammalian Daam1 was not evaluated. In this study, we used a mouse promoter trap technology to create Daam1 deficient mice to analyze the role of Daam1 in embryonic development and organogenesis. Daam1 is highly expressed in the developing heart. The majority of Daam1 mutant mice died between embryonic day 14.5 and birth, exhibiting a variety of heart defects, which include ventricular noncompaction, ventricular septal defects, and double outlet right ventricle. About 10% mutant mice survive to adulthood, and these survivors do not show significantly compromised heart function based on echocardiographic analyses. However, all of these mutant survivors have ventricular noncompaction with a range of severities. A conditional rescue experiment using a cardiac specific Cre mouse line, Nkx2-5Cre, confirmed that the cardiac defects are the primary cause of death in Daam1 mutants. Both in vivo and ex vivo analyses revealed that Daam1 is essential for regulating non-sarcomeric filamentous actin assembly in cardiomyocytes, which likely contributes to cardiac morphogenesis and ventricular wall maturation. Biochemical studies further suggested that Daam1 is not a key signaling component in regulating the activation of small GTPases, such as RhoA, Rac1 and Cdc42. In conclusion, our studies demonstrated that Daam1 is essential for cardiac morphogenesis likely through its regulation of cytoskeletal architecture in the developing cardiomyocytes.
Early severe coronary heart disease and ischemic heart failure in homozygous familial hypercholesterolemia: A case report
(Wolters Kluwer Health, 2018-10) Kuang, Hongyu; Zhou, Xue; Li, Li; Yi, Qijian; Shou, Weinian; Lu, Tiewei; Pediatrics, School of Medicine
RATIONALE: Familial hypercholesterolemia (FH) is a common inherited cause of coronary heart disease (CHD) and premature death in an early age. Nevertheless, an ischemic heart failure (IHF) associated with FH seems to be rare, and an early diagnosis and therapy could influence the prognosis. PATIENT CONCERNS: In this 13-year-old girl, multiple xanthomas began to develop from the first day of birth. Until June, 2017, she was admitted to our center due to edema, oliguria, and dyspnea during exertion, which was attributed to a recent respiratory infection. DIAGNOSIS: Homozygous FH (HoFH), CHD, and IHF. INTERVENTIONS: The patient has been treated with statin, ezetimibe, aspirin, and traditional heart failure (HF) medications. In addition, the beta-blocker was simultaneously administered. OUTCOMES: Genotypes of this proband indicated homozygous mutations of low-density lipoprotein receptor (LDLR) and some co-segregated mutations, such as von Willebrand factor (VWF) and fibroblast growth factor receptors. At 6-month follow-up, we found a decreased level of plasma lipid profile, in addition to a significant improvement in 6-minute walk distance and functional class. Echocardiography indicated nonsignificant improvements in the structure and function of the heart. LESSONS: This case report indicates that HoFH can lead to dramatically progressive endothelial damages and ventricular remodeling, severe atherosclerosis, even IHF. Genetic outcomes indicate IHF with HoFH could possibly result from LDLR mutations and some co-segregated mutations influencing endothelial function and cardiovascular remodeling. In a short-term follow-up, a combination of statins, ezetimibe, aspirin, and traditional HF agents is safe and effective for IHF with HoFH, and there is a need for further identification of drugs to ameliorate endothelial function and cardiovascular remodeling which may play an important role in long-term treatment.
The Emerging Roles of the RNA Binding Protein QKI in Cardiovascular Development and Function
(Frontiers Media, 2021-06-16) Chen, Xinyun; Yin, Jianwen; Cao, Dayan; Xiao, Deyong; Zhou, Zhongjun; Liu, Ying; Shou, Weinian; Pediatrics, School of Medicine
RNA binding proteins (RBPs) have a broad biological and physiological function and are critical in regulating pre-mRNA posttranscriptional processing, intracellular migration, and mRNA stability. QKI, also known as Quaking, is a member of the signal transduction and activation of RNA (STAR) family, which also belongs to the heterogeneous nuclear ribonucleoprotein K- (hnRNP K-) homology domain protein family. There are three major alternatively spliced isoforms, QKI-5, QKI-6, and QKI-7, differing in carboxy-terminal domains. They share a common RNA binding property, but each isoform can regulate pre-mRNA splicing, transportation or stability differently in a unique cell type-specific manner. Previously, QKI has been known for its important role in contributing to neurological disorders. A series of recent work has further demonstrated that QKI has important roles in much broader biological systems, such as cardiovascular development, monocyte to macrophage differentiation, bone metabolism, and cancer progression. In this mini-review, we will focus on discussing the emerging roles of QKI in regulating cardiac and vascular development and function and its potential link to cardiovascular pathophysiology.

Browsing by Author "Shou, Weinian"

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