Browsing by Author "Quertermous, Thomas"

Now showing 1 - 5 of 5
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    Epicardial calcineurin-NFAT signals through Smad2 to direct coronary smooth muscle cell and arterial wall development
    (Oxford University Press, 2014-01-01) Yang, Jin; Zeini, Miriam; Lin, Chieh-Yu; Chieh-Yu, Chien-Jung; Xiong, Yiqin; Shang, Ching; Han, Pei; Li, Wei; Quertermous, Thomas; Zhou, Bin; Chang, Ching-Pin; Department of Medicine, IU School of Medicine
    AIMS: Congenital coronary artery anomalies produce serious events that include syncope, arrhythmias, myocardial infarction, or sudden death. Studying the mechanism of coronary development will contribute to the understanding of the disease and help design new diagnostic or therapeutic strategies. Here, we characterized a new calcineurin-NFAT signalling which specifically functions in the epicardium to regulate the development of smooth muscle wall of the coronary arteries. METHODS AND RESULTS: Using tissue-specific gene deletion, we found that calcineurin-NFAT signals in the embryonic epicardium to direct coronary smooth muscle cell development. The smooth muscle wall of coronary arteries fails to mature in mice with epicardial deletion of calcineurin B1 (Cnb1), and accordingly these mutant mice develop cardiac dysfunction with reduced exercise capacity. Inhibition of calcineurin at various developmental windows shows that calcineurin-NFAT signals within a narrow time window at embryonic Day 12.5-13.5 to regulate coronary smooth muscle cell development. Within the epicardium, NFAT transcriptionally activates the expression of Smad2, whose gene product is critical for transducing transforming growth factor β (TGFβ)-Alk5 signalling to control coronary development. CONCLUSION: Our findings demonstrate new spatiotemporal and molecular actions of calcineurin-NFAT that dictate coronary arterial wall development and a new mechanism by which calcineurin-NFAT integrates with TGFβ signalling during embryonic development.
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    Epigenetic response to environmental stress: Assembly of BRG1–G9a/GLP–DNMT3 repressive chromatin complex on Myh6 promoter in pathologically stressed hearts
    (Elsevier, 2016-03-04) Han, Pei; Li, Wei; Yang, Jin; Shang, Ching; Lin, Chiou-Hong; Cheng, Wei; Hang, Calvin T.; Cheng, Hsiu-Ling; Chen, Chen-Hao; Wong, Johnson; Xiong, Yiqin; Zhao, Mingming; Drakos, Stavros G.; Ghetti, Andrea; Li, Dean Y.; Bernstein, Daniel; Chen, Huei-sheng Vincent; Quertermous, Thomas; Chang, Ching-Pin; Medicine, School of Medicine
    Chromatin structure is determined by nucleosome positioning, histone modifications, and DNA methylation. How chromatin modifications are coordinately altered under pathological conditions remains elusive. Here we describe a stress-activated mechanism of concerted chromatin modification in the heart. In mice, pathological stress activates cardiomyocytes to express Brg1 (nucleosome-remodeling factor), G9a/Glp (histone methyltransferase), and Dnmt3 (DNA methyltransferase). Once activated, Brg1 recruits G9a and then Dnmt3 to sequentially assemble repressive chromatin—marked by H3K9 and CpG methylation—on a key molecular motor gene (Myh6), thereby silencing Myh6 and impairing cardiac contraction. Disruption of Brg1, G9a or Dnmt3 erases repressive chromatin marks and de-represses Myh6, reducing stress-induced cardiac dysfunction. In human hypertrophic hearts, BRG1–G9a/GLP–DNMT3 complex is also activated; its level correlates with H3K9/CpG methylation, Myh6 repression, and cardiomyopathy. Our studies demonstrate a new mechanism of chromatin assembly in stressed hearts and novel therapeutic targets for restoring Myh6 and ventricular function. The stress-induced Brg1–G9a–Dnmt3 interactions and sequence of repressive chromatin assembly on Myh6 illustrates a molecular mechanism by which the heart epigenetically responds to environmental signals. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.
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    A long non-coding RNA protects the heart from pathological hypertrophy
    (Nature Publishing Group, 2014-10-02) Han, Pei; Li, Wei; Lin, Chiou-Hong; Yang, Jin; Shang, Ching; Nuernberg, Sylvia T.; Jin, Kevin Kai; Xu, Weihong; Lin, Chieh-Yu; Lin, Chien-Jung; Xiong, Yiqin; Chien, Huanchieh; Zhou, Bin; Ashley, Euan; Bernstein, Daniel; Chen, Peng-Sheng; Chen, Huei-sheng Vincent; Quertermous, Thomas; Chang, Ching-Pin; Department of Medicine, IU School of Medicine
    The role of long noncoding RNA (lncRNA) in adult hearts is unknown
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    Pathological Ace2-to-Ace enzyme switch in the stressed heart is transcriptionally controlled by the endothelial Brg1–FoxM1 complex
    (National Academy of Sciences, 2016-09-20) Yang, Jin; Feng, Xuhui; Zhou, Qiong; Cheng, Wei; Shang, Ching; Han, Pei; Lin, Chiou-Hong; Chen, Huei-Sheng Vincent; Quertermous, Thomas; Chang, Ching-Pin; Department of Medicine, IU School of Medicine
    Genes encoding angiotensin-converting enzymes (Ace and Ace2) are essential for heart function regulation. Cardiac stress enhances Ace, but suppresses Ace2, expression in the heart, leading to a net production of angiotensin II that promotes cardiac hypertrophy and fibrosis. The regulatory mechanism that underlies the Ace2-to-Ace pathological switch, however, is unknown. Here we report that the Brahma-related gene-1 (Brg1) chromatin remodeler and forkhead box M1 (FoxM1) transcription factor cooperate within cardiac (coronary) endothelial cells of pathologically stressed hearts to trigger the Ace2-to-Ace enzyme switch, angiotensin I-to-II conversion, and cardiac hypertrophy. In mice, cardiac stress activates the expression of Brg1 and FoxM1 in endothelial cells. Once activated, Brg1 and FoxM1 form a protein complex on Ace and Ace2 promoters to concurrently activate Ace and repress Ace2, tipping the balance to Ace2 expression with enhanced angiotensin II production, leading to cardiac hypertrophy and fibrosis. Disruption of endothelial Brg1 or FoxM1 or chemical inhibition of FoxM1 abolishes the stress-induced Ace2-to-Ace switch and protects the heart from pathological hypertrophy. In human hypertrophic hearts, BRG1 and FOXM1 expression is also activated in endothelial cells; their expression levels correlate strongly with the ACE/ACE2 ratio, suggesting a conserved mechanism. Our studies demonstrate a molecular interaction of Brg1 and FoxM1 and an endothelial mechanism of modulating Ace/Ace2 ratio for heart failure therapy.
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    Targeting LOXL2 for cardiac interstitial fibrosis and heart failure treatment
    (SpringerNature, 2016-12-14) Yang, Jin; Savvatis, Konstantinos; Kang, Jong Seok; Fan, Peidong; Zhong, Hongyan; Schwartz, Karen; Barry, Vivian; Mikels-Vigdal, Amanda; Karpinski, Serge; Kornyeyev, Dmytro; Adamkewicz, Joanne; Feng, Xuhui; Zhou, Qiong; Shang, Ching; Kumar, Praveen; Phan, Dillon; Kasner, Mario; Lopez, Begona; Diez, Javier; Wright, Keith C.; Kovacs, Roxanne L.; Chen, Peng-Sheng; Quertermous, Thomas; Smith, Victoria; Yao, Lina; Tschope, Carsten; Chang, Ching-Pin; Department of Medicine, IU School of Medicine
    Interstitial fibrosis plays a key role in the development and progression of heart failure. Here, we show that an enzyme that crosslinks collagen-Lysyl oxidase-like 2 (Loxl2)-is essential for interstitial fibrosis and mechanical dysfunction of pathologically stressed hearts. In mice, cardiac stress activates fibroblasts to express and secrete Loxl2 into the interstitium, triggering fibrosis, systolic and diastolic dysfunction of stressed hearts. Antibody-mediated inhibition or genetic disruption of Loxl2 greatly reduces stress-induced cardiac fibrosis and chamber dilatation, improving systolic and diastolic functions. Loxl2 stimulates cardiac fibroblasts through PI3K/AKT to produce TGF-β2, promoting fibroblast-to-myofibroblast transformation; Loxl2 also acts downstream of TGF-β2 to stimulate myofibroblast migration. In diseased human hearts, LOXL2 is upregulated in cardiac interstitium; its levels correlate with collagen crosslinking and cardiac dysfunction. LOXL2 is also elevated in the serum of heart failure (HF) patients, correlating with other HF biomarkers, suggesting a conserved LOXL2-mediated mechanism of human HF.