Browsing by Subject "Cardiac hypertrophy"

Now showing 1 - 6 of 6
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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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    Myofibroblast β2 adrenergic signaling amplifies cardiac hypertrophy in mice
    (Elsevier, 2019-02) Imaeda, Atsuki; Tanaka, Shota; Tonegawa, Kota; Fuchigami, Shota; Igarashi, Yumi; Takahashi, Misato; Enomoto, Daichi; Obana, Masanori; Maeda, Makiko; Kihara, Miho; Kiyonari, Hiroshi; Conway, Simon J.; Fujio, Yasushi; Nakayama, Hiroyuki; Pediatrics, School of Medicine
    Abnormal β-adrenergic signaling plays a central role in human heart failure. In mice, chronic β-adrenergic receptor (βAR) stimulation elicits cardiac hypertrophy. It has been reported that cultured cardiac fibroblasts express βAR; however, the functional in vivo requirement of βAR signaling in cardiac fibroblasts during the development of cardiac hypertrophy remains elusive. β2AR null mice exhibited attenuated hypertrophic responses to chronic βAR stimulation upon continuous infusion of an agonist, isoprenaline (ISO), compared to those in wildtype controls, suggesting that β2AR activation in the heart induces pro-hypertrophic effects in mice. Since β2AR signaling is protective in cardiomyocytes, we focused on β2AR signaling in cardiac myofibroblasts. To determine whether β2AR signaling in myofibroblasts affects cardiac hypertrophy, we generated myofibroblast-specific transgenic mice (TG) with the catalytic subunit of protein kinase A (PKAcα) using Cre-loxP system. Myofibroblast-specific PKAcα overexpression resulted in enhanced heart weight normalized to body weight ratio, associated with an enlargement of cardiomyocytes at 12 weeks of age, indicating that myofibroblast-specific activation of PKA mediates cardiac hypertrophy in mice. Neonatal rat cardiomyocytes stimulated with conditioned media from TG cardiac fibroblasts likewise exhibited significantly more growth than those from controls. Thus, β2AR signaling in myofibroblasts plays a substantial role in ISO-induced cardiac hypertrophy, possibly due to a paracrine effect. β2AR signaling in cardiac myofibroblasts may represent a promising target for development of novel therapies for cardiac hypertrophy.
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    Noncoding RNAs as Key Regulators for Cardiac Development and Cardiovascular Diseases
    (MDPI, 2023-04-12) Kawaguchi, Satoshi; Moukette, Bruno; Hayasaka, Taiki; Haskell, Angela K.; Mah, Jessica; Sepúlveda, Marisa N.; Tang, Yaoliang; Kim, Il-man; Anatomy, Cell Biology and Physiology, School of Medicine
    Noncoding RNAs (ncRNAs) play fundamental roles in cardiac development and cardiovascular diseases (CVDs), which are a major cause of morbidity and mortality. With advances in RNA sequencing technology, the focus of recent research has transitioned from studies of specific candidates to whole transcriptome analyses. Thanks to these types of studies, new ncRNAs have been identified for their implication in cardiac development and CVDs. In this review, we briefly describe the classification of ncRNAs into microRNAs, long ncRNAs, and circular RNAs. We then discuss their critical roles in cardiac development and CVDs by citing the most up-to-date research articles. More specifically, we summarize the roles of ncRNAs in the formation of the heart tube and cardiac morphogenesis, cardiac mesoderm specification, and embryonic cardiomyocytes and cardiac progenitor cells. We also highlight ncRNAs that have recently emerged as key regulators in CVDs by focusing on six of them. We believe that this review concisely addresses perhaps not all but certainly the major aspects of current progress in ncRNA research in cardiac development and CVDs. Thus, this review would be beneficial for readers to obtain a recent picture of key ncRNAs and their mechanisms of action in cardiac development and CVDs.
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    Novel Roles for Peroxynitrite in Angiotensin II and CaMKII Signaling
    (Nature Publishing Group, 2016) Zhou, Chaoming; Ramaswamy, Swarna S.; Johnson, Derrick E.; Vitturi, Dario A.; Schopfer, Franciso J.; Freeman, Bruce A.; Hudmon, Andy; Levitan, Edwin S.; Department of Biochemistry & Molecular Biology, IU School of Medicine
    Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) oxidation controls excitability and viability. While hydrogen peroxide (H2O2) affects Ca(2+)-activated CaMKII in vitro, Angiotensin II (Ang II)-induced CaMKIIδ signaling in cardiomyocytes is Ca(2+) independent and requires NADPH oxidase-derived superoxide, but not its dismutation product H2O2. To better define the biological regulation of CaMKII activation and signaling by Ang II, we evaluated the potential for peroxynitrite (ONOO(-)) to mediate CaMKII activation and downstream Kv4.3 channel mRNA destabilization by Ang II. In vitro experiments show that ONOO(-) oxidizes and modestly activates pure CaMKII in the absence of Ca(2+)/CaM. Remarkably, this apokinase stimulation persists after mutating known oxidation targets (M281, M282, C290), suggesting a novel mechanism for increasing baseline Ca(2+)-independent CaMKII activity. The role of ONOO(-) in cardiac and neuronal responses to Ang II was then tested by scavenging ONOO(-) and preventing its formation by inhibiting nitric oxide synthase. Both treatments blocked Ang II effects on Kv4.3, tyrosine nitration and CaMKIIδ oxidation and activation. Together, these data show that ONOO(-) participates in Ang II-CaMKII signaling. The requirement for ONOO(-) in transducing Ang II signaling identifies ONOO(-), which has been viewed as a reactive damaging byproduct of superoxide and nitric oxide, as a mediator of GPCR-CaMKII signaling.
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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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    Soluble α-klotho and heparin modulate the pathologic cardiac actions of fibroblast growth factor 23 in chronic kidney disease
    (Elsevier, 2022) Yanucil, Christopher; Kentrup, Dominik; Campos, Isaac; Czaya, Brian; Heitman, Kylie; Westbrook, David; Osis, Gunars; Grabner, Alexander; Wende, Adam R.; Vallejo, Julian; Wacker, Michael J.; Navarro-Garcia, Jose Alberto; Ruiz-Hurtado, Gema; Zhang, Fuming; Song, Yuefan; Linhardt, Robert J.; White, Kenneth; Kapiloff, Michael S.; Faul, Christian; Medical and Molecular Genetics, School of Medicine
    Fibroblast growth factor (FGF) 23 is a phosphate-regulating hormone that is elevated in patients with chronic kidney disease and associated with cardiovascular mortality. Experimental studies showed that elevated FGF23 levels induce cardiac hypertrophy by targeting cardiac myocytes via FGF receptor isoform 4 (FGFR4). A recent structural analysis revealed that the complex of FGF23 and FGFR1, the physiologic FGF23 receptor in the kidney, includes soluble α-klotho (klotho) and heparin, which both act as co-factors for FGF23/FGFR1 signaling. Here, we investigated whether soluble klotho, a circulating protein with cardio-protective properties, and heparin, a factor that is routinely infused into patients with kidney failure during the hemodialysis procedure, regulate FGF23/FGFR4 signaling and effects in cardiac myocytes. We developed a plate-based binding assay to quantify affinities of specific FGF23/FGFR interactions, and found that soluble klotho and heparin mediate FGF23 binding to distinct FGFR isoforms. Heparin specifically mediated FGF23 binding to FGFR4, and increased FGF23 stimulatory effects on hypertrophic growth and contractility in isolated cardiac myocytes. When repetitively injected into two different mouse models with elevated serum FGF23 levels, heparin aggravated cardiac hypertrophy. We also developed a novel procedure for the synthesis and purification of recombinant soluble klotho, which showed anti-hypertrophic effects in FGF23-treated cardiac myocytes. Thus, soluble klotho and heparin act as independent FGF23 coreceptors with opposite effects on the pathologic actions of FGF23, with soluble klotho reducing and heparin increasing FGF23-induced cardiac hypertrophy. Hence, whether heparin injections during hemodialysis in patients with extremely high serum FGF23 levels contribute to their high rates of cardiovascular events and mortality remains to be studied.