Publications

2020
Jinmiao Chen, Qing Ma, Justin S King, Yan Sun, Bing Xu, Xiaoyu Zhang, Sylvia Zohrabian, Haipeng Guo, Wenqing Cai, Gavin Li, Ivone Bruno, John P Cooke, Chunsheng Wang, Maria Kontaridis, Da-Zhi Wang, Hongbo Luo, William T Pu, and Zhiqiang Lin. 2020. “aYAP modRNA reduces cardiac inflammation and hypertrophy in a murine ischemia-reperfusion model.” Life Sci Alliance, 3, 1.Abstract
Myocardial recovery from ischemia-reperfusion (IR) is shaped by the interaction of many signaling pathways and tissue repair processes, including the innate immune response. We and others previously showed that sustained expression of the transcriptional co-activator yes-associated protein (YAP) improves survival and myocardial outcome after myocardial infarction. Here, we asked whether transient YAP expression would improve myocardial outcome after IR injury. After IR, we transiently activated YAP in the myocardium with modified mRNA encoding a constitutively active form of YAP (aYAP modRNA). Histological studies 2 d after IR showed that aYAP modRNA reduced cardiomyocyte (CM) necrosis and neutrophil infiltration. 4 wk after IR, aYAP modRNA-treated mice had better heart function as well as reduced scar size and hypertrophic remodeling. In cultured neonatal and adult CMs, YAP attenuated HO- or LPS-induced CM necrosis. TLR signaling pathway components important for innate immune responses were suppressed by YAP/TEAD1. In summary, our findings demonstrate that aYAP modRNA treatment reduces CM necrosis, cardiac inflammation, and hypertrophic remodeling after IR stress.
Tábatha de Oliveira Silva, Caroline A Lino, Vanessa C Buzatto, Paula Fontes Asprino, Yao Wei Lu, Vanessa M Lima, Renata IB Fonseca, Leonardo Jensen, Gilson M Murata, Sidney V Filho, Márcio AC Ribeiro, Jose Jr Donato, Julio CB Ferreira, Alice C Rodrigues, Maria Cláudia Irigoyen, Maria Luiza M Barreto-Chaves, Zhan-Peng Huang, Pedro Favoretto A Galante, Da-Zhi Wang, and Gabriela P Diniz. 2020. “Deletion of miRNA-22 Induces Cardiac Hypertrophy in Females but Attenuates Obesogenic Diet-Mediated Metabolic Disorders.” Cell Physiol Biochem, 54, 6, Pp. 1199-1217.Abstract
BACKGROUND/AIMS: Obesity is a risk factor associated with cardiometabolic complications. Recently, we reported that miRNA-22 deletion attenuated high-fat diet-induced adiposity and prevented dyslipidemia without affecting cardiac hypertrophy in male mice. In this study, we examined the impact of miRNA-22 in obesogenic diet-induced cardiovascular and metabolic disorders in females. METHODS: Wild type (WT) and miRNA-22 knockout (miRNA-22 KO) females were fed a control or an obesogenic diet. Body weight gain, adiposity, glucose tolerance, insulin tolerance, and plasma levels of total cholesterol and triglycerides were measured. Cardiac and white adipose tissue remodeling was assessed by histological analyses. Echocardiography was used to evaluate cardiac function and morphology. RNA-sequencing analysis was employed to characterize mRNA expression profiles in female hearts. RESULTS: Loss of miRNA-22 attenuated body weight gain, adiposity, and prevented obesogenic diet-induced insulin resistance and dyslipidemia in females. WT obese females developed cardiac hypertrophy. Interestingly, miRNA-22 KO females displayed cardiac hypertrophy without left ventricular dysfunction and myocardial fibrosis. Both miRNA-22 deletion and obesogenic diet changed mRNA expression profiles in female hearts. Enrichment analysis revealed that genes associated with regulation of the force of heart contraction, protein folding and fatty acid oxidation were enriched in hearts of WT obese females. In addition, genes related to thyroid hormone responses, heart growth and PI3K signaling were enriched in hearts of miRNA-22 KO females. Interestingly, miRNA-22 KO obese females exhibited reduced mRNA levels of Yap1, Egfr and Tgfbr1 compared to their respective controls. CONCLUSION: This study reveals that miRNA-22 deletion induces cardiac hypertrophy in females without affecting myocardial function. In addition, our findings suggest miRNA-22 as a potential therapeutic target to treat obesity-related metabolic disorders in females.
Yunzhou Dong, Yang Lee, Kui Cui, Ming He, Beibei Wang, Sudarshan Bhattacharjee, Bo Zhu, Tadayuki Yago, Kun Zhang, Lin Deng, Kunfu Ouyang, Aiyun Wen, Douglas B Cowan, Kai Song, Lili Yu, Megan L Brophy, Xiaolei Liu, Jill Wylie-Sears, Hao Wu, Scott Wong, Guanglin Cui, Yusuke Kawashima, Hiroyuki Matsumoto, Yoshio Kodera, Richard JH Wojcikiewicz, Sanjay Srivastava, Joyce Bischoff, Da-Zhi Wang, Klaus Ley, and Hong Chen. 2020. “Epsin-mediated degradation of IP3R1 fuels atherosclerosis.” Nat. Commun., 11, 1, Pp. 3984.Abstract
The epsin family of endocytic adapter proteins are widely expressed, and interact with both proteins and lipids to regulate a variety of cell functions. However, the role of epsins in atherosclerosis is poorly understood. Here, we show that deletion of endothelial epsin proteins reduces inflammation and attenuates atherosclerosis using both cell culture and mouse models of this disease. In atherogenic cholesterol-treated murine aortic endothelial cells, epsins interact with the ubiquitinated endoplasmic reticulum protein inositol 1,4,5-trisphosphate receptor type 1 (IP3R1), which triggers proteasomal degradation of this calcium release channel. Epsins potentiate its degradation via this interaction. Genetic reduction of endothelial IP3R1 accelerates atherosclerosis, whereas deletion of endothelial epsins stabilizes IP3R1 and mitigates inflammation. Reduction of IP3R1 in epsin-deficient mice restores atherosclerotic progression. Taken together, epsin-mediated degradation of IP3R1 represents a previously undiscovered biological role for epsin proteins and may provide new therapeutic targets for the treatment of atherosclerosis and other diseases.
Yunzhou Dong, Yang Lee, Kui Cui, Ming He, Beibei Wang, Sudarshan Bhattacharjee, Bo Zhu, Tadayuki Yago, Kun Zhang, Lin Deng, Kunfu Ouyang, Aiyun Wen, Douglas B Cowan, Kai Song, Lili Yu, Megan L Brophy, Xiaolei Liu, Jill Wylie-Sears, Hao Wu, Scott Wong, Guanglin Cui, Yusuke Kawashima, Hiroyuki Matsumoto, Yoshio Kodera, Richard JH Wojcikiewicz, Sanjay Srivastava, Joyce Bischoff, Da-Zhi Wang, Klaus Ley, and Hong Chen. 2020. “Epsin-mediated degradation of IP3R1 fuels atherosclerosis.” Nat Commun, 11, 1, Pp. 3984.Abstract
The epsin family of endocytic adapter proteins are widely expressed, and interact with both proteins and lipids to regulate a variety of cell functions. However, the role of epsins in atherosclerosis is poorly understood. Here, we show that deletion of endothelial epsin proteins reduces inflammation and attenuates atherosclerosis using both cell culture and mouse models of this disease. In atherogenic cholesterol-treated murine aortic endothelial cells, epsins interact with the ubiquitinated endoplasmic reticulum protein inositol 1,4,5-trisphosphate receptor type 1 (IP3R1), which triggers proteasomal degradation of this calcium release channel. Epsins potentiate its degradation via this interaction. Genetic reduction of endothelial IP3R1 accelerates atherosclerosis, whereas deletion of endothelial epsins stabilizes IP3R1 and mitigates inflammation. Reduction of IP3R1 in epsin-deficient mice restores atherosclerotic progression. Taken together, epsin-mediated degradation of IP3R1 represents a previously undiscovered biological role for epsin proteins and may provide new therapeutic targets for the treatment of atherosclerosis and other diseases.
Haipeng Guo, Yao Wei Lu, Zhiqiang Lin, Zhan-Peng Huang, Jianming Liu, Yi Wang, Hee Young Seok, Xiaoyun Hu, Qing Ma, Kathryn Li, Jan Kyselovic, Qingchuan Wang, Jenny L-C Lin, Jim J-C Lin, Douglas B Cowan, Francisco Naya, Yuguo Chen, William T Pu, and Da-Zhi Wang. 2020. “Intercalated disc protein Xinβ is required for Hippo-YAP signaling in the heart.” Nat Commun, 11, 1, Pp. 4666.Abstract
Intercalated discs (ICD), specific cell-to-cell contacts that connect adjacent cardiomyocytes, ensure mechanical and electrochemical coupling during contraction of the heart. Mutations in genes encoding ICD components are linked to cardiovascular diseases. Here, we show that loss of Xinβ, a newly-identified component of ICDs, results in cardiomyocyte proliferation defects and cardiomyopathy. We uncovered a role for Xinβ in signaling via the Hippo-YAP pathway by recruiting NF2 to the ICD to modulate cardiac function. In Xinβ mutant hearts levels of phosphorylated NF2 are substantially reduced, suggesting an impairment of Hippo-YAP signaling. Cardiac-specific overexpression of YAP rescues cardiac defects in Xinβ knock-out mice-indicating a functional and genetic interaction between Xinβ and YAP. Our study reveals a molecular mechanism by which cardiac-expressed intercalated disc protein Xinβ modulates Hippo-YAP signaling to control heart development and cardiac function in a tissue specific manner. Consequently, this pathway may represent a therapeutic target for the treatment of cardiovascular diseases.
Emre Bektik, Douglas B Cowan, and Da-Zhi Wang. 2020. “Long Non-Coding RNAs in Atrial Fibrillation: Pluripotent Stem Cell-Derived Cardiomyocytes as a Model System.” Int. J. Mol. Sci., 21, 15.Abstract
Atrial fibrillation (AF) is a type of sustained arrhythmia in humans often characterized by devastating alterations to the cardiac conduction system as well as the structure of the atria. AF can lead to decreased cardiac function, heart failure, and other complications. Long non-coding RNAs (lncRNAs) have been shown to play important roles in the cardiovascular system, including AF; however, a large group of lncRNAs is not conserved between mouse and human. Furthermore, AF has complex networks showing variations in mechanisms in different species, making it challenging to utilize conventional animal models to investigate the functional roles and potential therapeutic benefits of lncRNAs for AF. Fortunately, pluripotent stem cell (PSC)-derived cardiomyocytes (CMs) offer a reliable platform to study lncRNA functions in AF because of certain electrophysiological and molecular similarities with native human CMs. In this review, we first summarize the broad aspects of lncRNAs in various heart disease settings, then focus on their potential roles in AF development and pathophysiology. We also discuss current uses of PSCs in AF research and describe how these studies could be developed into novel therapeutics for AF and other cardiovascular diseases.
Emre Bektik, Douglas B Cowan, and Da-Zhi Wang. 2020. “Long Non-Coding RNAs in Atrial Fibrillation: Pluripotent Stem Cell-Derived Cardiomyocytes as a Model System.” Int J Mol Sci, 21, 15.Abstract
Atrial fibrillation (AF) is a type of sustained arrhythmia in humans often characterized by devastating alterations to the cardiac conduction system as well as the structure of the atria. AF can lead to decreased cardiac function, heart failure, and other complications. Long non-coding RNAs (lncRNAs) have been shown to play important roles in the cardiovascular system, including AF; however, a large group of lncRNAs is not conserved between mouse and human. Furthermore, AF has complex networks showing variations in mechanisms in different species, making it challenging to utilize conventional animal models to investigate the functional roles and potential therapeutic benefits of lncRNAs for AF. Fortunately, pluripotent stem cell (PSC)-derived cardiomyocytes (CMs) offer a reliable platform to study lncRNA functions in AF because of certain electrophysiological and molecular similarities with native human CMs. In this review, we first summarize the broad aspects of lncRNAs in various heart disease settings, then focus on their potential roles in AF development and pathophysiology. We also discuss current uses of PSCs in AF research and describe how these studies could be developed into novel therapeutics for AF and other cardiovascular diseases.
Tian Liang, Feng Gao, Jun Jiang, Yao Wei Lu, Feng Zhang, Yingchao Wang, Ning Liu, Xuyang Fu, Xiaoxuan Dong, Jianqiu Pei, Douglas B Cowan, Xinyang Hu, Jian'an Wang, Da-Zhi Wang, and Jinghai Chen. 2020. “Loss of Phosphatase and Tensin Homolog Promotes Cardiomyocyte Proliferation and Cardiac Repair After Myocardial Infarction.” Circulation, 142, 22, Pp. 2196-2199.
Jianming Liu, Zhan-Peng Huang, Mao Nie, Gang Wang, William J Silva, Qiumei Yang, Paula P Freire, Xiaoyun Hu, Huaqun Chen, Zhongliang Deng, William T Pu, and Da-Zhi Wang. 2020. “Regulation of myonuclear positioning and muscle function by the skeletal muscle-specific CIP protein.” Proc Natl Acad Sci U S A, 117, 32, Pp. 19254-19265.Abstract
The appropriate arrangement of myonuclei within skeletal muscle myofibers is of critical importance for normal muscle function, and improper myonuclear localization has been linked to a variety of skeletal muscle diseases, such as centronuclear myopathy and muscular dystrophies. However, the molecules that govern myonuclear positioning remain elusive. Here, we report that skeletal muscle-specific CIP (sk-CIP) is a regulator of nuclear positioning. Genetic deletion of sk-CIP in mice results in misalignment of myonuclei along the myofibers and at specialized structures such as neuromuscular junctions (NMJs) and myotendinous junctions (MTJs) in vivo, impairing myonuclear positioning after muscle regeneration, leading to severe muscle dystrophy in mice, a mouse model of Duchenne muscular dystrophy. sk-CIP is localized to the centrosome in myoblasts and relocates to the outer nuclear envelope in myotubes upon differentiation. Mechanistically, we found that sk-CIP interacts with the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex and the centriole Microtubule Organizing Center (MTOC) proteins to coordinately modulate myonuclear positioning and alignment. These findings indicate that sk-CIP may function as a muscle-specific anchoring protein to regulate nuclear position in multinucleated muscle cells.
Jianming Liu, Zhan-Peng Huang, Mao Nie, Gang Wang, William J Silva, Qiumei Yang, Paula P Freire, Xiaoyun Hu, Huaqun Chen, Zhongliang Deng, William T Pu, and Da-Zhi Wang. 2020. “Regulation of myonuclear positioning and muscle function by the skeletal muscle-specific CIP protein.” Proc. Natl. Acad. Sci. U. S. A.Abstract
The appropriate arrangement of myonuclei within skeletal muscle myofibers is of critical importance for normal muscle function, and improper myonuclear localization has been linked to a variety of skeletal muscle diseases, such as centronuclear myopathy and muscular dystrophies. However, the molecules that govern myonuclear positioning remain elusive. Here, we report that skeletal muscle-specific CIP (sk-CIP) is a regulator of nuclear positioning. Genetic deletion of sk-CIP in mice results in misalignment of myonuclei along the myofibers and at specialized structures such as neuromuscular junctions (NMJs) and myotendinous junctions (MTJs) in vivo, impairing myonuclear positioning after muscle regeneration, leading to severe muscle dystrophy in mdx mice, a mouse model of Duchenne muscular dystrophy. sk-CIP is localized to the centrosome in myoblasts and relocates to the outer nuclear envelope in myotubes upon differentiation. Mechanistically, we found that sk-CIP interacts with the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex and the centriole Microtubule Organizing Center (MTOC) proteins to coordinately modulate myonuclear positioning and alignment. These findings indicate that sk-CIP may function as a muscle-specific anchoring protein to regulate nuclear position in multinucleated muscle cells.
Gurinder Bir Singh, Douglas B Cowan, and Da-Zhi Wang. 2020. “Tiny Regulators of Massive Tissue: MicroRNAs in Skeletal Muscle Development, Myopathies, and Cancer Cachexia.” Front Oncol, 10, Pp. 598964.Abstract
Skeletal muscles are the largest tissues in our body and the physiological function of muscle is essential to every aspect of life. The regulation of development, homeostasis, and metabolism is critical for the proper functioning of skeletal muscle. Consequently, understanding the processes involved in the regulation of myogenesis is of great interest. Non-coding RNAs especially microRNAs (miRNAs) are important regulators of gene expression and function. MiRNAs are small (~22 nucleotides long) noncoding RNAs known to negatively regulate target gene expression post-transcriptionally and are abundantly expressed in skeletal muscle. Gain- and loss-of function studies have revealed important roles of this class of small molecules in muscle biology and disease. In this review, we summarize the latest research that explores the role of miRNAs in skeletal muscle development, gene expression, and function as well as in muscle disorders like sarcopenia and Duchenne muscular dystrophy (DMD). Continuing with the theme of the current review series, we also briefly discuss the role of miRNAs in cancer cachexia.
María Salazar-Roa, Marianna Trakala, Mónica Álvarez-Fernández, Fátima Valdés-Mora, Cuiqing Zhong, Jaime Muñoz, Yang Yu, Timothy J Peters, Osvaldo Graña-Castro, Rosa Serrano, Elisabet Zapatero-Solana, María Abad, María José Bueno, Marta Gómez de Cedrón, José Fernández-Piqueras, Manuel Serrano, María A Blasco, Da-Zhi Wang, Susan J Clark, Juan Carlos Izpisua-Belmonte, Sagrario Ortega, and Marcos Malumbres. 2020. “Transient exposure to miR-203 enhances the differentiation capacity of established pluripotent stem cells.” EMBO J, 39, 16, Pp. e104324.Abstract
Full differentiation potential along with self-renewal capacity is a major property of pluripotent stem cells (PSCs). However, the differentiation capacity frequently decreases during expansion of PSCs in vitro. We show here that transient exposure to a single microRNA, expressed at early stages during normal development, improves the differentiation capacity of already-established murine and human PSCs. Short exposure to miR-203 in PSCs (miPSCs) induces a transient expression of 2C markers that later results in expanded differentiation potency to multiple lineages, as well as improved efficiency in tetraploid complementation and human-mouse interspecies chimerism assays. Mechanistically, these effects are at least partially mediated by direct repression of de novo DNA methyltransferases Dnmt3a and Dnmt3b, leading to transient and reversible erasure of DNA methylation. These data support the use of transient exposure to miR-203 as a versatile method to reset the epigenetic memory in PSCs, and improve their effectiveness in regenerative medicine.
Jun Cao, Douglas B Cowan, and Da-Zhi Wang. 2020. “tRNA-Derived Small RNAs and Their Potential Roles in Cardiac Hypertrophy.” Front Pharmacol, 11, Pp. 572941.Abstract
Transfer RNAs (tRNAs) are abundantly expressed, small non-coding RNAs that have long been recognized as essential components of the protein translation machinery. The tRNA-derived small RNAs (tsRNAs), including tRNA halves (tiRNAs), and tRNA fragments (tRFs), were unexpectedly discovered and have been implicated in a variety of important biological functions such as cell proliferation, cell differentiation, and apoptosis. Mechanistically, tsRNAs regulate mRNA destabilization and translation, as well as retro-element reverse transcriptional and post-transcriptional processes. Emerging evidence has shown that tsRNAs are expressed in the heart, and their expression can be induced by pathological stress, such as hypertrophy. Interestingly, cardiac pathophysiological conditions, such as oxidative stress, aging, and metabolic disorders can be viewed as inducers of tsRNA biogenesis, which further highlights the potential involvement of tsRNAs in these conditions. There is increasing enthusiasm for investigating the molecular and biological functions of tsRNAs in the heart and their role in cardiovascular disease. It is anticipated that this new class of small non-coding RNAs will offer new perspectives in understanding disease mechanisms and may provide new therapeutic targets to treat cardiovascular disease.
María Salazar-Roa, Marianna Trakala, Mónica Álvarez-Fernández, Fátima Valdés-Mora, Cuiqing Zhong, Jaime Muñoz, Yang Yu, Timothy J Peters, Osvaldo Graña-Castro, Rosa Serrano, Elisabet Zapatero-Solana, María Abad, María José Bueno, Marta Gómez de Cedrón, José Fernández-Piqueras, Manuel Serrano, María A Blasco, Da-Zhi Wang, Susan J Clark, Juan Carlos Izpisua-Belmonte, Sagrario Ortega, and Marcos Malumbres. 2020. “Transient exposure to miR-203 enhances the differentiation capacity of established pluripotent stem cells.” EMBO J., Pp. e104324.Abstract
Full differentiation potential along with self-renewal capacity is a major property of pluripotent stem cells (PSCs). However, the differentiation capacity frequently decreases during expansion of PSCs in vitro. We show here that transient exposure to a single microRNA, expressed at early stages during normal development, improves the differentiation capacity of already-established murine and human PSCs. Short exposure to miR-203 in PSCs (miPSCs) induces a transient expression of 2C markers that later results in expanded differentiation potency to multiple lineages, as well as improved efficiency in tetraploid complementation and human-mouse interspecies chimerism assays. Mechanistically, these effects are at least partially mediated by direct repression of de novo DNA methyltransferases Dnmt3a and Dnmt3b, leading to transient and reversible erasure of DNA methylation. These data support the use of transient exposure to miR-203 as a versatile method to reset the epigenetic memory in PSCs, and improve their effectiveness in regenerative medicine.
2019
Gao F, Kataoka M, Liu N, Liang T, Huang ZP, Gu F, Ding J, Liu J, Zhang F, Ma Q, Wang Y, Zhang M, Hu X, Kyselovic J, Hu X, Pu WT, Wang J, Chen J, and Wang DZ. 4/17/2019. “Therapeutic role of miR-19a/19b in cardiac regeneration and protection from myocardial infarction.” Nat Commun, 2019, 10, 1, Pp. 1802. Publisher's VersionAbstract
The primary cause of heart failure is the loss of cardiomyocytes in the diseased adult heart. Previously, we reported that the miR-17-92 cluster plays a key role in cardiomyocyte proliferation. Here, we report that expression of miR-19a/19b, members of the miR-17-92 cluster, is induced in heart failure patients. We show that intra-cardiac injection of miR-19a/19b mimics enhances cardiomyocyte proliferation and stimulates cardiac regeneration in response to myocardial infarction (MI) injury. miR-19a/19b protected the adult heart in two distinctive phases: an early phase immediately after MI and long-term protection. Genome-wide transcriptome analysis demonstrates that genes related to the immune response are repressed by miR-19a/19b. Using an adeno-associated virus approach, we validate that miR-19a/19b reduces MI-induced cardiac damage and protects cardiac function. Finally, we confirm the therapeutic potential of miR-19a/19b in protecting cardiacfunction by systemically delivering miR-19a/19b into mice post-MI. Our study establishes miR-19a/19b as potential therapeutic targets to treat heart failure.    
Zhou Q, Yu B, Anderson C, Huang ZP, Hanus J, Zhang W, Han Y, Peters DC, Bhattacharjee PS, Srinivasan S, Zhang K, Wang DZ, and Wang S. 2/11/2019. “LncEGFL7OS regulates human angiogenesis by interacting with MAX at the EGFL7/miR-126 locus.” Elife. 2019 Feb 11;, 8. Publisher's VersionAbstract
In an effort to identify human endothelial cell (EC)-enriched lncRNAs,~500 lncRNAs were shown to be highly restricted in primary humanECs. Among them, lncEGFL7OS, located in the opposite strand of the EGFL7/miR-126 gene, is regulated by ETS factors through a bidirectional promoter in ECs. It is enriched in highly vascularized human tissues, and upregulated in the hearts of dilated cardiomyopathy patients. LncEGFL7OS silencing impairs angiogenesis as shown by EC/fibroblast co-culture, in vitro/in vivo and ex vivo human choroid sprouting angiogenesis assays, while lncEGFL7OS overexpression has the opposite function. Mechanistically, lncEGFL7OS is required for MAPK and AKT pathway activation by regulating EGFL7/miR-126 expression. MAX protein was identified as a lncEGFL7OS-interactingprotein that functions to regulate histone acetylation in the EGFL7/miR-126 promoter/enhancer. CRISPR-mediated targeting of EGLF7/miR-126/lncEGFL7OS locus inhibits angiogenesis, inciting therapeutic potential of targeting this locus. Our study establishes lncEGFL7OS as a human/primate-specific EC-restricted lncRNA critical for human angiogenesis. 
Chuanwei Li, Zhangxue Hu, Wen Zhang, Junyi Yu, Yang Yang, Zaicheng Xu, Hao Luo, Xiaoli Liu, Yukai Liu, Caiyu Chen, Yue Cai, Xuewei Xia, Xiaoqun Zhang, Da-Zhi Wang, Gengze Wu, and Chunyu Zeng. 2019. “Regulation of Cholesterol Homeostasis by a Novel Long Non-coding RNA LASER.” Scientific reports, 9, 1, Pp. 7693-7693. Publisher's VersionAbstract
Genome-wide association studies (GWAS) have identified many genetic variants in genes related to lipid metabolism. However, how these variations affect lipid levels remains elusive. Long non-coding RNAs (lncRNAs) have been implicated in a variety of biological processes. We hypothesize lncRNAs are likely to be located within disease or trait-associated DNA regions to regulate lipid metabolism. The aim of this study was to investigate whether and how lncRNAs in lipid- associated DNA regions regulate cholesterol homeostasis in hepatocytes. In this study, we identified a novel long non-coding RNA in Lipid Associated Single nucleotide polymorphism gEne Region (LASER) by bioinformatic analysis. We report that LASER is highly expressed in both hepatocytes and peripheral mononuclear cells (PBMCs). Clinical studies showed that LASER expression is positively related with that of cholesterol containing apolipoprotein levels. In particular, we found that LASER is positively correlated with plasma PCSK9 levels in statin free patients. siRNAs mediated knock down of LASER dramatically reduces intracellular cholesterol levels and affects the expression of genes involved in cholesterol metabolism. Transcriptome analyses show that knockdown of LASER affects the expression of genes involved in metabolism pathways. We found that HNF-1a and PCSK9 were reduced after LASER knock-down. Interestingly, the reduction of PCSK9 can be blocked by the treatment of berberine, a natural cholesterol-lowering compound which functions as a HNF-1a antagonist. Mechanistically, we found that LASER binds to LSD1 (lysine-specific demethylase 1), a member of CoREST/REST complex, in nucleus. LASER knock-down enhance LSD1 targeting to genomic loci, resulting in decreased histone H3 lysine 4 mono-methylation at the promoter regions of HNF-1a gene. Conversely, LSD1 knock-down abolished the effect of LASER on HNF-1a and PCSK9 expressions. Finally, we found that statin treatment increased LASER expression, accompanied with increased PCSK9 expression, suggesting a feedback regulation of cholesterol on LASER expression. This observation may partly explain the statin escape during anti-cholesterol treatment. These findings identified a novel lncRNA in cholesterol homeostasis. Therapeutic targeting LASER might be an effective approach to augment the effect of statins on cholesterol levels in clinics.
2018
Lu YW and Wang DZ. 9/26/2018. “Non-coding RNA in Ischemic and Non-ischemic Cardiomyopathy.” Curr Cardiol Rep. 2018 Sep 26;, 20, 11, Pp. 115. Publisher's VersionAbstract

PURPOSE OF REVIEW:

This review aims to summarize and discuss the function and molecular mechanism of miRNA and lncRNA in the heart, focusing on ischemic and non-ischemic cardiomyopathy.

RECENT FINDINGS:

Extensive studies in the past decades have identified numerous protein-coding genes that are highly expressed in the heart, playing essential roles in the regulation of cardiac gene expression, heart development, and function. Furthermore, mutations in many of these genes have been identified and are linked to cardiovascular disease. Intriguingly, it is now recognized that majority of our genome is "non-coding," which produces a large amount of non-coding RNAs (ncRNAs), including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). Emerging evidence has indicated that these classes of non-coding RNAs participate in most (if not all) aspects of cardiac gene expression, cardiomyocyte proliferation, differentiation, and cardiac remodeling in response to stress. Recent findings have demonstrated important functions for non-coding RNA in ischemic and non-ischemic cardiomyopathy. It is expected that non-coding RNAs will become promising therapeutic targets for cardiovascular diseases.

KEYWORDS:

Heart failure; Ischemic cardiomyopathy; Non-ischemic cardiomyopathy; lncRNA; miRNA

Huang ZP and Wang DZ. 4/24/2018. “miR-22 in Smooth Muscle Cells: A Potential Therapy for Cardiovascular Disease.” Circulation. 2018, 137, 17, Pp. 1842–1845. Publisher's VersionAbstract
Cardiovascular disease (CVD) continues to be the leading cause of death and disability in the United States. Furthermore, over 40% of the US adult population is projected to have some form of CVD by 2030. Vascular smooth muscle cells (VSMCs) participate importantly in atherosclerosis, the major cause of myocardial infarction and stroke. MicroRNAs (miRNAs) are a class of small non-coding RNAs containing ~22 nucleotides. Studies using mouse models have shown that miRNAs are essential for cardiovascular development and function. Furthermore, miRNAs are required for proliferation and differentiation of VSMCs during embryonic development and for maintaining vascular contractile function, SMC contractile differentiation, and vascular remodeling in the postnatal stage. Numerous studies have linked altered miRNA expression to various diseases, indicating that miRNAs may play important roles in the pathogenesis of CVD.
Zhang D, Li Y, Heims-Waldron D, Bezzerides V, Guatimosim S, Guo Y, Gu F, Zhou P, Lin Z, Ma Q, Liu J, Wang DZ, and Pu WT. 1/5/2018. “Mitochondrial Cardiomyopathy Caused by Elevated Reactive Oxygen Species and Impaired Cardiomyocyte Proliferation.” Circ Res. 2018 Jan 05;, 122, 1, Pp. 74–87. Publisher's VersionAbstract

RATIONALE:

Although mitochondrial diseases often cause abnormal myocardial development, the mechanisms by which mitochondria influence heart growth and function are poorly understood.

OBJECTIVE:

To investigate these disease mechanisms, we studied a genetic model of mitochondrial dysfunction caused by inactivation of Tfam (transcription factor A, mitochondrial), a nuclear-encoded gene that is essential for mitochondrial gene transcription and mitochondrialDNA replication.

METHODS AND RESULTS:

Tfam inactivation by Nkx2.5Cre caused mitochondrial dysfunction and embryonic lethal myocardial hypoplasia. Tfam inactivation was accompanied by elevated production of reactive oxygen species (ROS) and reduced cardiomyocyte proliferation. Mosaic embryonic Tfam inactivation confirmed that the block to cardiomyocyte proliferation was cell autonomous. Transcriptional profiling by RNA-seq demonstrated the activation of the DNA damage pathway. Pharmacological inhibition of ROS or the DNA damage response pathway restored cardiomyocyte proliferation in cultured fetal cardiomyocytes. Neonatal Tfam inactivation by AAV9-cTnT-Cre causedprogressive, lethal dilated cardiomyopathy. Remarkably, postnatal Tfam inactivation and disruption of mitochondrial function did not impair cardiomyocyte maturation. Rather, it elevated ROS production, activated the DNA damage response pathway, and decreased cardiomyocyteproliferation. We identified a transient window during the first postnatal week when inhibition of ROS or the DNA damage response pathway ameliorated the detrimental effect of Tfam inactivation.

CONCLUSIONS:

Mitochondrial dysfunction caused by Tfam inactivation induced ROS production, activated the DNA damage response, and caused cardiomyocyte cell cycle arrest, ultimately resulting in lethal cardiomyopathy. Normal mitochondrial function was not required for cardiomyocyte maturation. Pharmacological inhibition of ROS or DNA damage response pathways is a potential strategy to prevent cardiac dysfunction caused by some forms of mitochondrial dysfunction.

 

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