Abstract 278: Cardiac Med1 is Necessary for Postnatal Survival in Mice

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Kathryn M Spitler ◽  
Jessica M Ponce ◽  
Duane D Hall ◽  
Chad E Grueter
Keyword(s):  
Cardiovascular Disease ◽  
Cardiac Function ◽  
Gene Transcription ◽  
Cardiac Development ◽  
Critical Role ◽  
Cardiac Contractility ◽  
Mediator Complex ◽  
Cardiomyocyte Hypertrophy ◽  
And Function

Alterations in gene transcription are commonly associated with cardiovascular disease pathogenesis characterized by cardiomyocyte hypertrophy. The phenotypic responses result in diminished cardiac contractility, ventricular dilation, fibrosis and ultimately sudden death. The mediator complex is a crucial facilitator of gene transcription; however, few studies have investigated the role of mediator in cardiovascular disease initiation and progression. A key subunit of the Mediator complex, MED1, interacts with nuclear receptors to target gene-specific transcription. To determine the role of MED1 in regulating cardiac function, we generated a heart specific knockout of MED1 (cMED1KO). Postnatal deletion of MED1 in mice results in lethality between 3 to 6 weeks of age. The cMED1KO mice display a marked increase in heart mass compared to floxed controls. Furthermore, echocardiography and histological analysis of hearts taken at 3 weeks showed that the cMED1KO animals had decreased cardiac function, increased fibrosis and a dilated left ventricle. Transcriptional changes were observed for key markers of cardiac disease including MYH7, ANF, ACTIN1. We performed RNAseq analysis to identify changes in the transciptome between cMED1KO and floxed control hearts. The analysis unveiled changes in expression of genes regulating cardiac development, metabolism and function. Taken together these results reveal a critical role for MED1 in postnatal cardiac growth and development due to altered gene expression in adult cardiomyocytes.

Abstract 791: A Critical Role for Bmper (BMP-binding Endothelial cell precursor-derived Regulator) in Cardiac Muscle Mass Regulation during Development and Pressure Overload Induced Hypertrophy

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Monte Willis ◽  
Rongqin Ren ◽  
Cam Patterson
Keyword(s):  
Cardiac Function ◽  
Cardiac Muscle ◽  
Muscle Mass ◽  
Cardiac Development ◽  
Critical Role ◽  
Pressure Overload ◽  
Posterior Wall ◽  
Fractional Shortening

Bone morphogenetic proteins (BMPs) of the TGF-beta superfamily, have been implicated in multiple processes during cardiac development. Our laboratory recently described an unprecedented role for Bmper in antagonizing BMP-2, BMP-4, and BMP-6. To determine the role of Bmper on cardiac development in vivo, we created Bmper null (Bmper −/−) mice by replacing exons 1 and 2 with GFP. Since Bmper −/− mice are perinatally lethal, we determined pre-natal cardiac function of Bmper −/− mice in utero just before birth. By echocardiography, E18.5 Bmper −/− embryos had decreased cardiac function (24.2 +/− 8.1% fractional shortening) compared to Bmper +/− and Bmper +/+ siblings (52.2 +/− 1.6% fractional shortening) (N=4/group). To further characterize the role of Bmper on cardiac function in adult mice, we performed echocardiography on 8-week old male and female Bmper +/− and littermate control Bmper +/+. Bmper +/− mice had an approximately 15% decrease in anterior and posterior wall thickness compared to sibling Bmper +/+ mice at baseline (n=10/group). Cross-sectional areas of Bmper +/− cardiomyocytes were approximately 20% less than wild type controls, indicating cardiomyocyte hypoplasia in adult Bmper +/− mice at baseline. Histologically, no significant differences were identified in representative H&E and trichrome stained adult Bmper +/− and Bmper +/+ cardiac sections at baseline. To determine the effects of Bmper expression on the development of cardiac hypertrophy, both Bmper +/− and Bmper +/+ sibling controls underwent transaortic constriction (TAC), followed by weekly echocardiography. While a deficit was identified in Bmper +/− mice at baseline, both anterior and posterior wall thicknesses increased after TAC, such that identical wall thicknesses were identified in Bmper +/− and Bmper +/+ mice 1–4 weeks after TAC. Notably, cardiac function (fractional shortening %) and histological evaluation revealed no differences between Bmper +/− and Bmper +/+ any time after TAC. These studies identify for the first time that Bmper expression plays a critical role in regulating cardiac muscle mass during development, and that Bmper regulates the development of hypertrophy in response to pressure overload in vivo.

Myocardial extra-cellular matrix and its regulation by metalloproteinases and their inhibitors

2005 ◽  
Vol 93 (02) ◽  
pp. 212-219 ◽  
Author(s):  
Zamaneh Kassiri ◽  
Rama Khokha
Keyword(s):  
Heart Failure ◽  
Cardiac Development ◽  
Critical Role ◽  
Left Ventricular ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Western World ◽  
A Disintegrin And Metalloproteinase ◽  
And Function ◽  
Myocardial Injuries

SummaryCardiovascular disease poses a major health care burden in the Western world. Following myocardial injuries, ventricular remodelling and dysfunction ensue, which can eventually culminate in heart failure. An important event in left ventricular (LV) remodelling is alteration of the extracellular matrix (ECM) integrity, the structural network that interconnects the myocardial components. The critical role of ECM remodelling in cardiac dilation and heart failure was recognized more than a decade ago, and the molecular factors responsible for this process are now being explored. Abnormal ECM turnover is primarily brought about by an imbalance in the activity of matrix metalloproteinases (MMPs) that degrade ECM components, and their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMPs). Here we provide an overview of composition of the cardiac ECM, and alterations in ECM regulatory proteins, MMPs and TIMPs, in human heart disease. We also discuss the role of TIMPs, MMPs, and a disintegrin and metalloproteinase (ADAMs) enzymes in cardiac development and function as learned through genetically altered mouse models.

scholarly journals LncRNA HBL1 is required for genome-wide PRC2 occupancy and function in cardiogenesis from human pluripotent stem cells

Development ◽  
2021 ◽  
Author(s):  
Juli Liu ◽  
Sheng Liu ◽  
Lei Han ◽  
Yi Sheng ◽  
Yucheng Zhang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Gene Transcription ◽  
Pluripotent Stem Cells ◽  
Cardiac Development ◽  
Chromatin Modification ◽  
Human Pluripotent Stem Cells ◽  
Cardiac Differentiation ◽  
Genome Wide ◽  
And Function

Polycomb Repressive Complex 2 (PRC2) deposits H3K27me3 on chromatin to silence transcription. PRC2 broadly interacts with RNAs. Currently, the role of RNA- PRC2 interaction in human cardiogenesis remains elusive. Here, we found human-specific Heart Brake LncRNA 1 (HBL1) interacted with two PRC2 subunits, JARID2 and EED, in human pluripotent stem cells (hPSCs). Loss-of-JARID2, EED or HBL1 significantly enhanced cardiac differentiation from hPSCs. HBL1 depletion disrupted genome-wide PRC2 occupancy and H3K27me3 chromatin modification on essential cardiogenic genes, and broadly enhanced cardiogenic gene transcription in undifferentiated hPSCs and later-on differentiation. Additionally, ChIP-seq revealed reduced EED-occupancy on 62 overlapped cardiogenic genes in HBL1−/- and JARID2−/- hPSCs, indicating the epigenetic state of cardiogenic genes was determined by HBL1 and JARID2 at pluripotency stage. Furthermore, after cardiac development occurred, the cytosolic and nuclear fractions of HBL1 could crosstalk via a conserved “microRNA-1-JARID2” axis to modulate cardiogenic gene transcription. Overall, our findings delineate the indispensable role of HBL1 in guiding PRC2 function during early human cardiogenesis, and expand the mechanistic scope of lncRNA(s) that cytosolic and nuclear portions of HBL1 could coordinate to orchestrate human cardiogenesis.

scholarly journals Abnormal Cardiac Development in the Absence of Heart Glycogen

2004 ◽  
Vol 24 (16) ◽  
pp. 7179-7187 ◽  
Author(s):  
Bartholomew A. Pederson ◽  
Hanying Chen ◽  
Jill M. Schroeder ◽  
Weinian Shou ◽  
Anna A. DePaoli-Roach ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Cardiac Muscle ◽  
Heart Development ◽  
Congenital Heart ◽  
Cardiac Development ◽  
Glycogen Synthase ◽  
Heart Defects ◽  
Mendelian Inheritance ◽  
And Function ◽  
Impaired Cardiac Function

ABSTRACT Glycogen serves as a repository of glucose in many mammalian tissues. Mice lacking this glucose reserve in muscle, heart, and several other tissues were generated by disruption of the GYS1 gene, which encodes an isoform of glycogen synthase. Crossing mice heterozygous for the GYS1 disruption resulted in a significant underrepresentation of GYS1-null mice in the offspring. Timed matings established that Mendelian inheritance was followed for up to 18.5 days postcoitum (dpc) and that ∼90% of GYS1-null animals died soon after birth due to impaired cardiac function. Defects in cardiac development began between 11.5 and 14.5 dpc. At 18.5 dpc, the hearts were significantly smaller, with reduced ventricular chamber size and enlarged atria. Consistent with impaired cardiac function, edema, pooling of blood, and hemorrhagic liver were seen. Glycogen synthase and glycogen were undetectable in cardiac muscle and skeletal muscle from the surviving null mice, and the hearts showed normal morphology and function. Congenital heart disease is one of the most common birth defects in humans, at up to 1 in 50 live births. The results provide the first direct evidence that the ability to synthesize glycogen in cardiac muscle is critical for normal heart development and hence that its impairment could be a significant contributor to congenital heart defects.

A Review on Role of Macro and Micro Banking Environment on Non-Performing Assets Management

2019 ◽  
pp. 281-294
Author(s):  
Biswajit Prasad Chhatoi ◽  
Sharada Prasad Sahoo
Keyword(s):  
Critical Role ◽  
Banking System ◽  
Financial Assets ◽  
Policy Changes ◽  
Public And Private ◽  
Private Banks ◽  
Specific Factors ◽  
And Function ◽  
Asset Creation

In a self-resilient economy, banking system assumes importance in imparting momentum to economic growth and prosperity through mobilization of financial assets. Performance of banks, irrespective of their nature and function, is germane to their asset creation and maintenance capacity. In a neo-liberal regime, radical policy changes have crept into loan mechanism, thereby subjecting the banks to efficiently recover the loans, which is a vital asset for any banking firm. In this context, the authors through intensive review of literature identified micro and macro banking factors responsible for productive NPA management. The macro banking factors refer to the economic environment whereas the micro banking factors refer to the bank and branch-specific factors. The authors identified the critical role of organizational structure, involvement of employees, and organizational efficiency in driving prudent NPA management. The authors have found that the efficiency in managing NPAs differ in public and private banks, which is attributed to involvement of employees.

scholarly journals Atypical ALPK2 kinase is not essential for cardiac development and function

2020 ◽  
Vol 318 (6) ◽  
pp. H1509-H1515
Author(s):  
Julius Bogomolovas ◽  
Wei Feng ◽  
Matthew Daniel Yu ◽  
Serena Huang ◽  
Lunfeng Zhang ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Cardiac Development ◽  
Cardiac Defects ◽  
Cardiac Phenotype ◽  
Cardiac Functions ◽  
And Function

Several studies indicated the importance of ALPK2 for cardiac function and development. A recent study in zebrafish report that loss of ALPK2 leads to severe cardiac defects. In contrast, murine Alpk2-gKO models developed in this work display no overt cardiac phenotype. Our results suggest ALPK2, as a rapidly evolving gene, lost its essential cardiac functions in mammals.

scholarly journals Deletion of Cardiomyocyte Glycogen Synthase Kinase-3 Beta (GSK-3β) Improves Systemic Glucose Tolerance with Maintained Heart Function in Established Obesity

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1120 ◽  
Author(s):  
Manisha Gupte ◽  
Prachi Umbarkar ◽  
Anand Prakash Singh ◽  
Qinkun Zhang ◽  
Sultan Tousif ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Glycogen Synthase ◽  
Critical Role ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Total Period ◽  
Gsk 3Β

Obesity is an independent risk factor for cardiovascular diseases (CVD), including heart failure. Thus, there is an urgent need to understand the molecular mechanism of obesity-associated cardiac dysfunction. We recently reported the critical role of cardiomyocyte (CM) Glycogen Synthase Kinase-3 beta (GSK-3β) in cardiac dysfunction associated with a developing obesity model (deletion of CM-GSK-3β prior to obesity). In the present study, we investigated the role of CM-GSK-3β in a clinically more relevant model of established obesity (deletion of CM-GSK-3β after established obesity). CM-GSK-3β knockout (GSK-3βfl/flCre+/−) and controls (GSK-3βfl/flCre−/−) mice were subjected to a high-fat diet (HFD) in order to establish obesity. After 12 weeks of HFD treatment, all mice received tamoxifen injections for five consecutive days to delete GSK-3β specifically in CMs and continued on the HFD for a total period of 55 weeks. To our complete surprise, CM-GSK-3β knockout (KO) animals exhibited a globally improved glucose tolerance and maintained normal cardiac function. Mechanistically, in stark contrast to the developing obesity model, deleting CM-GSK-3β in obese animals did not adversely affect the GSK-3αS21 phosphorylation (activity) and maintained canonical β-catenin degradation pathway and cardiac function. As several GSK-3 inhibitors are in the trial to treat various chronic conditions, including metabolic diseases, these findings have important clinical implications. Specifically, our results provide critical pre-clinical data regarding the safety of GSK-3 inhibition in obese patients.

scholarly journals Cardiac Development and Transcription Factors: Insulin Signalling, Insulin Resistance, and Intrauterine Nutritional Programming of Cardiovascular Disease

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Annelene Govindsamy ◽  
Strinivasen Naidoo ◽  
Marlon E. Cerf
Keyword(s):  
Insulin Resistance ◽  
Cardiovascular Disease ◽  
Transcription Factors ◽  
Cardiac Development ◽  
Insulin Signalling ◽  
Life Stages ◽  
Sequential Process ◽  
Insulin Resistant ◽  
Sensitive Organ ◽  
And Function

Programming with an insult or stimulus during critical developmental life stages shapes metabolic disease through divergent mechanisms. Cardiovascular disease increasingly contributes to global morbidity and mortality, and the heart as an insulin-sensitive organ may become insulin resistant, which manifests as micro- and/or macrovascular complications due to diabetic complications. Cardiogenesis is a sequential process during which the heart develops into a mature organ and is regulated by several cardiac-specific transcription factors. Disrupted cardiac insulin signalling contributes to cardiac insulin resistance. Intrauterine under- or overnutrition alters offspring cardiac structure and function, notably cardiac hypertrophy, systolic and diastolic dysfunction, and hypertension that precede the onset of cardiovascular disease. Optimal intrauterine nutrition and oxygen saturation are required for normal cardiac development in offspring and the maintenance of their cardiovascular physiology.

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