scholarly journals LARP7 Protects Against Heart Failure by Enhancing Mitochondrial Biogenesis

Circulation ◽  
2021 ◽  
Author(s):  
Huijing Yu ◽  
Fang Zhang ◽  
Pengyi Yan ◽  
Shasha Zhang ◽  
Yingmei Lou ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Dna Damage ◽  
Oxidative Phosphorylation ◽  
Cardiac Function ◽  
Dna Damage Response ◽  
Mitochondrial Biogenesis ◽  
Virus Serotype ◽  
Damage Response ◽  
Human Primate

Background: Heart failure (HF) is among the leading causes of morbidity and mortality, and its prevalence continues to rise. La ribonucleoprotein domain family member 7 (LARP7) is a master regulator that governs the DNA damage response and RNAPII pausing pathway, but the role of it in heart failure pathogenesis is incompletely understood. Methods: We assessed LARP7 expression in human HF, and in non-human primate and mouse HF models. To study the function of LARP7 in heart, we generated global and cardiac-specific LARP7 knockout mice. We acutely abolished LARP7 in mature cardiomyocytes by Cas9-mediated LARP7 somatic knockout. We overexpressed LARP7 in cardiomyocytes using adeno-associated virus serotype 9 (AAV9) and ataxia telangiectasia mutated protein (ATM) inhibitor. The therapeutic potential of LARP7-regulated pathways in heart failure was tested in a mouse myocardial infarction model. Results: LARP7 was profoundly downregulated in failing human hearts and in non-human primate and murine hearts after myocardial infarction (MI). Low LARP7 levels in failing hearts was linked to elevated reactive oxygen species (ROS), which activated the ATM-mediated DNA damage response pathway and promoted LARP7 ubiquitination and degradation. Constitutive LARP7 knockout in mouse resulted in impaired mitochondrial biogenesis, myocardial hypoplasia, and midgestational lethality. Cardiac-specific inactivation resulted in defective mitochondrial biogenesis, impaired oxidative phosphorylation, elevated oxidative stress and HF by 4 months of age. These abnormalities were accompanied by reduced SIRT1 stability and deacetylase activity which impaired SIRT1-mediated transcription of genes for oxidative phosphorylation and energy metabolism and dampened cardiac function. Restoring LARP7 expression after MI by either AAV-mediated LARP7 expression or small molecule ATM inhibitor substantially improved the function of injured heart. Conclusions: LARP7 is essential for mitochondrial biogenesis, energy production and cardiac function by modulating SIRT1 homeostasis and activity. Reduction of LARP7 in diseased hearts due to activation of the ATM pathway contributes to heart failure pathogenesis, and restoring LARP7 in the injured heart confers myocardial protection. These results identify the ATM-LARP7-SIRT1 pathway as a target for therapeutic intervention in heart failure.

Abstract 15981: DNA Single-strand Break-induced DNA Damage Response Causes Heart Failure

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Tomoaki Higo ◽  
Atsuhiko Naito ◽  
Masato Shibamoto ◽  
Jong-Kook Lee ◽  
Shungo Hikoso ◽  
...  
Keyword(s):  
Heart Failure ◽  
Dna Damage ◽  
Inflammatory Cytokines ◽  
Dna Damage Response ◽  
Nuclear Translocation ◽  
Pressure Overload ◽  
Strand Break ◽  
Single Strand Break ◽  
Failing Heart ◽  
Damage Response

Introduction: The DNA damage response (DDR) pathway is activated upon DNA damage. In mitotic cells, the DDR plays essential role in maintaining genomic stability and preventing cancer formation. DNA damage and activation of the DDR are also observed in the post-mitotic cardiomyocytes of patients with end-stage heart failure, however, their roles in the pathogenesis of heart failure remains elusive. Methods and Results: We performed transverse aortic constriction (TAC) operation to produce mice model of pressure-overload induced heart failure. Alkaline- and neutral- comet assay revealed that unrepaired DNA single-strand break (SSB), not double-strand break, is accumulated in cardiomyocytes of the failing heart. Mice with cardiomyocyte-specific deletion of XRCC1, a scaffold protein essential for SSB repair, exhibited more severe heart failure and higher mortality after TAC operation. Knockdown of Xrcc1 using siRNA produced SSB accumulation in cardiomyocytes and SSB accumulation induced persistent DDR through activation of ataxia telangiectasia mutated (ATM) kinase. Activated ATM also induced nuclear translocation of NF-κB and increased the expression of inflammatory cytokines. Activation of DDR, nuclear translocation of NF-κB, and increased expression of inflammatory cytokines were also observed in the failing heart and were enhanced in the heart of cardiomyocyte-specific XRCC1 knockout mice. Conclusions: Unrepaired DNA SSB accumulates in post-mitotic cardiomyocytes and plays a pathogenic role in pressure overload-induced heart failure. Approaches that promote efficient SSB repair or suppress aberrant activation of DDR pathway may become a novel therapeutic strategy against heart failure.

scholarly journals DNA single-strand break-induced DNA damage response causes heart failure

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Tomoaki Higo ◽  
Atsuhiko T. Naito ◽  
Tomokazu Sumida ◽  
Masato Shibamoto ◽  
Katsuki Okada ◽  
...  
Keyword(s):  
Heart Failure ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Strand Break ◽  
Single Strand ◽  
Single Strand Break ◽  
Damage Response

scholarly journals Moderate and high amounts of tamoxifen in  MHC-MerCreMer mice induce a DNA damage response, leading to heart failure and death

2013 ◽  
Vol 6 (6) ◽  
pp. 1459-1469 ◽  
Author(s):  
K. Bersell ◽  
S. Choudhury ◽  
M. Mollova ◽  
B. D. Polizzotti ◽  
B. Ganapathy ◽  
...  
Keyword(s):  
Heart Failure ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Damage Response

scholarly journals Activation of DNA Damage Response and Cellular Senescence in Cardiac Fibroblasts Limit Cardiac Fibrosis After Myocardial Infarction

2019 ◽  
Vol 60 (4) ◽  
pp. 944-957 ◽  
Author(s):  
Masato Shibamoto ◽  
Tomoaki Higo ◽  
Atsuhiko T. Naito ◽  
Akito Nakagawa ◽  
Tomokazu Sumida ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Cellular Senescence ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Damage Response

scholarly journals Pathogenic role of DNA single-strand break accumulation and DNA damage response in pressure overload-induced heart failure

2018 ◽  
Vol WCP2018 (0) ◽  
pp. OR2-4
Author(s):  
Atsuhiko T. Naito ◽  
Tomoaki Higo ◽  
Hiroko Izumi-Nakaseko ◽  
Kentaro Ando ◽  
Mihoko Hagiwara-Nagasawa ◽  
...  
Keyword(s):  
Heart Failure ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Pressure Overload ◽  
Strand Break ◽  
Single Strand ◽  
Pathogenic Role ◽  
Single Strand Break ◽  
Damage Response

Gene Expression Changes in CD34+ Cells Precede Development of Therapy-Related Leukemia (t-MDS/AML) After Autologous Hematopoietic Cell Transplantation (aHCT) for Hodgkin (HL) or Non-Hodgkin Lymphoma (NHL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 677-677
Author(s):  
Liang Li ◽  
Min Li ◽  
Can-Lan Sun ◽  
Melanie D. Sabado ◽  
Liton Francisco ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Dna Damage ◽  
Oxidative Phosphorylation ◽  
Dna Damage Response ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Gene Set ◽  
Gene Sets ◽  
Cd34 Cells ◽  
Damage Response

Abstract Abstract 677 t-MDS/AML is a lethal complication of aHCT for HL and NHL. The pathogenesis of t-MDS/AML is unclear. We are addressing this gap by conducting a prospective study of patients undergoing aHCT for HL/ NHL at City of Hope, with serial collection of biospecimens from pre-aHCT to 5 years after aHCT (Figure). In this report we describe alterations in gene expression (analyzed using Affymetrix HG-U133 plus 2.0 arrays) in CD34+ hematopoietic stem and progenitor cells (HSPC) associated with development of t-MDS/AML. Patients who developed t-MDS/AML after aHCT (”cases”) were compared with patients who did not develop t-MDS/AML after aHCT (“controls”: matched for primary diagnosis, age, race/ethnicity, and time since aHCT). CD34+ cells were selected from specimens obtained at the following time points: 1) pre-aHCT: peripheral blood stem cell (PBSC) product; and 2) at time of t-MDS/AML for cases and comparable time for controls: bone marrow (BM). Conditional logistic model was used to identify differences in gene expression between cases and controls in: 1) PBSC samples (18 patients who subsequently developed t-MDS/AML [cases]; 37 who did not [controls]); 2) BM samples at time of t-MDS/AML (12 cases; 21 controls); and 3) changes in gene expression from PBSC to t-MDS/AML (Figure). Gene Set Enrichment Analysis (GSEA) showed that PBSC from patients that later developed t-MDS/AML showed significant downregulation of gene sets related to mitochondria and oxidative phosphorylation, ribosomes, tRNA synthesis, proteasome, late progenitors and cell cycle (FDR<10-5for each) and upregulation of genes related to G-protein coupled receptors (GPCR, FDR=0.003) and hematopoietic regulation (CEBP, HOX, Hedgehog, FDR=0.003, 0.04, 0.06 respectively). These pathway alterations were confirmed by Ingenuity and Gene Ontology analysis. BM CD34+ cells obtained at t-MDS/AML showed downregulation of gene sets for cell cycle, p21 and p53 signaling and late progenitors (FDR<10-5 for each) and upregulation of gene sets for GPCR and cell communication/adhesion (FDR<10-5). Analysis of changes in gene expression from PBSC to t-MDS/AML revealed that compared to the controls, the cases demonstrated increased expression of mitochondrial and ribosomal gene sets and reduced expression of DNA damage response and cell cycle regulation gene sets. These results show that specific abnormalities in gene expression associated with t-MDS/AML are present in HSPC long before the development of clinical disease, and that other gene expression abnormalities occur later in the course of disease development. Indeed 22 of the top 50 upregulated and 20 of the top 50 downregulated gene sets at t-MDS/AML were represented within the top 50 up- and down-regulated sets prior to aHCT in the PBSC sample. A gene set comprised of genes differentially expressed between cases and controls at t-MDS/AML was significantly enriched amongst genes differentially expressed in PBSC (NES= -1.74, P = 0.003, FDR=0.024), further demonstrating that gene expression abnormalities associated with t-MDS/AML were present at the time of PBSC collection. To explore the hypothesis that reduced mitochondrial oxidative phosphorylation may lead to enhanced generation of reactive oxygen species (ROS) and oxidative damage, we measured ROS levels in PBSC in untreated cells and after VP16 exposure. ROS level were increased at baseline in PBSC CD34+ cells from t-MDS/AML cases compared to controls (P=0.003) and ROS elimination after VP16 exposure was reduced (P=0.05, 2 hours after VP-16 treatment). The observed gene expression changes support a model for t-MDS/AML development in which 1) reduced mitochondrial oxidative phosphorylation leads to increased ROS levels and increased damage to HSPC following therapeutic exposures, and 2) subsequent loss of DNA damage response and cell cycle regulatory mechanisms in damaged HSPC leads to the emergence of t-MDS/AML. Disclosures: No relevant conflicts of interest to declare.

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