Publications by authors named "Federica Accornero"

35 Publications

Pyridostigmine improves cardiac function and rhythmicity through RyR2 stabilization and inhibition of STIM1-mediated calcium entry in heart failure.

J Cell Mol Med 2021 Mar 23. Epub 2021 Mar 23.

Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH, USA.

Heart failure (HF) is characterized by asymmetrical autonomic balance. Treatments to restore parasympathetic activity in human heart failure trials have shown beneficial effects. However, mechanisms of parasympathetic-mediated improvement in cardiac function remain unclear. The present study examined the effects and underpinning mechanisms of chronic treatment with the cholinesterase inhibitor, pyridostigmine (PYR), in pressure overload HF induced by transverse aortic constriction (TAC) in mice. TAC mice exhibited characteristic adverse structural (left ventricular hypertrophy) and functional remodelling (reduced ejection fraction, altered myocyte calcium (Ca) handling, increased arrhythmogenesis) with enhanced predisposition to arrhythmogenic aberrant sarcoplasmic reticulum (SR) Ca release, cardiac ryanodine receptor (RyR2) hyper-phosphorylation and up-regulated store-operated Ca entry (SOCE). PYR treatment resulted in improved cardiac contractile performance and rhythmic activity relative to untreated TAC mice. Chronic PYR treatment inhibited altered intracellular Ca handling by alleviating aberrant Ca release and diminishing pathologically enhanced SOCE in TAC myocytes. At the molecular level, these PYR-induced changes in Ca handling were associated with reductions of pathologically enhanced phosphorylation of RyR2 serine-2814 and STIM1 expression in HF myocytes. These results suggest that chronic cholinergic augmentation alleviates HF via normalization of both canonical RyR2-mediated SR Ca release and non-canonical hypertrophic Ca signaling via STIM1-dependent SOCE.
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http://dx.doi.org/10.1111/jcmm.16356DOI Listing
March 2021

Micro-dystrophin gene therapy prevents heart failure in an improved Duchenne muscular dystrophy cardiomyopathy mouse model.

JCI Insight 2021 Apr 8;6(7). Epub 2021 Apr 8.

Department of Physiology & Cell Biology and Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, Ohio, USA.

Gene replacement for Duchenne muscular dystrophy (DMD) with micro-dystrophins has entered clinical trials, but efficacy in preventing heart failure is unknown. Although most patients with DMD die from heart failure, cardiomyopathy is undetectable until the teens, so efficacy from trials in young boys will be unknown for a decade. Available DMD animal models were sufficient to demonstrate micro-dystrophin efficacy on earlier onset skeletal muscle pathology underlying loss of ambulation and respiratory insufficiency in patients. However, no mouse models progressed into heart failure, and dog models showed highly variable progression insufficient to evaluate efficacy of micro-dystrophin or other therapies on DMD heart failure. To overcome this barrier, we have generated the first DMD mouse model to our knowledge that reproducibly progresses into heart failure. This model shows cardiac inflammation and fibrosis occur prior to reduced function. Fibrosis does not continue to accumulate, but inflammation persists after function declines. We used this model to test micro-dystrophin gene therapy efficacy on heart failure prevention for the first time. Micro-dystrophin prevented declines in cardiac function and prohibited onset of inflammation and fibrosis. This model will allow identification of committed pathogenic steps to heart failure and testing of genetic and nongenetic therapies to optimize cardiac care for patients with DMD.
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http://dx.doi.org/10.1172/jci.insight.146511DOI Listing
April 2021

Paracardial fat remodeling affects systemic metabolism through alcohol dehydrogenase 1.

J Clin Invest 2021 Feb;131(4)

Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA.

The relationship between adiposity and metabolic health is well established. However, very little is known about the fat depot, known as paracardial fat (pCF), located superior to and surrounding the heart. Here, we show that pCF remodels with aging and a high-fat diet and that the size and function of this depot are controlled by alcohol dehydrogenase 1 (ADH1), an enzyme that oxidizes retinol into retinaldehyde. Elderly individuals and individuals with obesity have low ADH1 expression in pCF, and in mice, genetic ablation of Adh1 is sufficient to drive pCF accumulation, dysfunction, and global impairments in metabolic flexibility. Metabolomics analysis revealed that pCF controlled the levels of circulating metabolites affecting fatty acid biosynthesis. Also, surgical removal of the pCF depot was sufficient to rescue the impairments in cardiometabolic flexibility and fitness observed in Adh1-deficient mice. Furthermore, treatment with retinaldehyde prevented pCF remodeling in these animals. Mechanistically, we found that the ADH1/retinaldehyde pathway works by driving PGC-1α nuclear translocation and promoting mitochondrial fusion and biogenesis in the pCF depot. Together, these data demonstrate that pCF is a critical regulator of cardiometabolic fitness and that retinaldehyde and its generating enzyme ADH1 act as critical regulators of adipocyte remodeling in the pCF depot.
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http://dx.doi.org/10.1172/JCI141799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880313PMC
February 2021

Microfibrillar-Associated Protein 4 Regulates Stress-Induced Cardiac Remodeling.

Circ Res 2021 Mar 3;128(6):723-737. Epub 2021 Feb 3.

Physiology and Cell Biology (L.E.D., W.L., J.M.P., M.S.S., P.M.L.J., P.J.M., F.A.), The Ohio State University Wexner Medical Center, Columbus.

[Figure: see text].
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http://dx.doi.org/10.1161/CIRCRESAHA.120.317146DOI Listing
March 2021

Remodeling of the mA landscape in the heart reveals few conserved post-transcriptional events underlying cardiomyocyte hypertrophy.

J Mol Cell Cardiol 2021 02 12;151:46-55. Epub 2020 Nov 12.

Department of Physiology & Cell Biology, Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University, Wexner Medical Center, Columbus, OH, USA. Electronic address:

Regulation of gene expression plays a fundamental role in cardiac stress-responses. Modification of coding transcripts by adenosine methylation (mA) has recently emerged as a critical post-transcriptional mechanism underlying heart disease. Thousands of mammalian mRNAs are known to be mA-modified, suggesting that remodeling of the mA landscape may play an important role in cardiac pathophysiology. Here we found an increase in mA content in human heart failure samples. We then adopted genome-wide analysis to define all mA-regulated sites in human failing compared to non-failing hearts and identified targeted transcripts involved in histone modification as enriched in heart failure. Further, we compared all mA sites regulated in human hearts with the ones occurring in isolated rat hypertrophic cardiomyocytes to define cardiomyocyte-specific mA events conserved across species. Our results identified 38 shared transcripts targeted by mA during stress conditions, and 11 events that are unique to unstressed cardiomyocytes. Of these, further evaluation of select mRNA and protein abundances demonstrates the potential impact of mA on post-transcriptional regulation of gene expression in the heart.
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http://dx.doi.org/10.1016/j.yjmcc.2020.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880874PMC
February 2021

From canonical to modified nucleotides: balancing translation and metabolism.

Crit Rev Biochem Mol Biol 2020 Dec 16;55(6):525-540. Epub 2020 Sep 16.

The Center for RNA Biology, The Ohio State University, Columbus, OH, USA.

Every type of nucleic acid in cells may undergo some kind of post-replicative or post-transcriptional chemical modification. Recent evidence has highlighted their importance in biology and their chemical complexity. In the following pages, we will describe new discoveries of modifications, with a focus on tRNA and mRNA. We will highlight current challenges and advances in modification detection and we will discuss how changes in nucleotide post-transcriptional modifications may affect cell homeostasis leading to malfunction. Although, RNA modifications prevail in all forms of life, the present review will focus on eukaryotic systems, where the great degree of intracellular compartmentalization provides barriers and filters for the level at which a given RNA is modified and will of course affect its fate and function. Additionally, although we will mention rRNA modification and modifications of the mRNA 5'-CAP structure, this will only be discussed in passing, as many substantive reviews have been written on these subjects. Here we will not spend much time describing all the possible modifications that have been observed; truly a daunting task. For reference, Bujnicki and coworkers have created MODOMICS, a useful repository for all types of modifications and their associated enzymes. Instead we will discuss a few examples, which illustrate our arguments on the connection of modifications, metabolism and ultimately translation. The fact remains, a full understanding of the long reach of nucleic acid modifications in cells requires both a global and targeted study of unprecedented scale, which at the moment may well be limited only by technology.
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http://dx.doi.org/10.1080/10409238.2020.1818685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703805PMC
December 2020

Epitranscriptomics in the Heart: a Focus on mA.

Curr Heart Fail Rep 2020 10;17(5):205-212

Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, 473 W 12th Ave, Columbus, OH, 43210, USA.

Purpose Of Review: Post-transcriptional modifications are key regulators of gene expression that allow the cell to respond to environmental stimuli. The most abundant internal mRNA modification is N6-methyladenosine (mA), which has been shown to be involved in the regulation of RNA splicing, localization, translation, and decay. It has also been implicated in a wide range of diseases, and here, we review recent evidence of mA's involvement in cardiac pathologies and processes.

Recent Findings: Studies have primarily relied on gain and loss of function models for the enzymes responsible for adding and removing the mA modification. Results have revealed a multifaceted role for mA in the heart's response to myocardial infarction, pressure overload, and ischemia/reperfusion injuries. Genome-wide analyses of mRNAs that are differentially methylated during cardiac stress have highlighted the importance of mA in regulating the translation of specific categories of transcripts implicated in pathways such as calcium handling, cell growth, autophagy, and adrenergic signaling in cardiomyocytes. Regulation of gene expression by mA is critical for cardiomyocyte homeostasis and stress responses, suggesting a key role for this modification in cardiac pathophysiology.
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http://dx.doi.org/10.1007/s11897-020-00473-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486268PMC
October 2020

Phase Separation and Disorder-to-Order Transition of Human Brain Expressed X-Linked 3 (hBEX3) in the Presence of Small Fragments of tRNA.

J Mol Biol 2020 03 3;432(7):2319-2348. Epub 2020 Mar 3.

Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil; Plataforma Avançada de Biomoléculas, Centro Nacional de Biologia Estrutural e Bioimagem, Universidade Federal do Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil. Electronic address:

Brain Expressed X-linked (BEX) protein family consists of five members in humans and is highly expressed during neuronal development. They are known to participate in cell cycle and in signaling pathways involved in neurodegeneration and cancer. BEX3 possess a conserved leucine-rich nuclear export signal and experimental data confirmed BEX3 nucleocytoplasmic shuttling. Previous data revealed that mouse BEX3 auto-associates in an oligomer rich in intrinsic disorder. In this work, we show that human BEX3 (hBEX3) has well-defined three-dimensional structure in the presence of small fragments of tRNA (tRFs). Conversely, the nucleic acids-free purified hBEX3 presented disordered structure. Small-angle X-ray scattering data revealed that in the presence of tRFs, hBEX3 adopts compact globular fold, which is very distinct from the elongated high-order oligomer formed by the pure protein. Furthermore, microscopy showed that hBEX3 undergoes condensation in micron-sized protein-rich droplets in vitro. In the presence of tRFs, biomolecular condensates were smaller and in higher number, showing acridine orange green fluorescence emission, which corroborated with the presence of base-paired nucleic acids. Additionally, we found that over time hBEX3 transits from liquid condensates to aggregates that are reversible upon temperature increment and dissolved by 1,6-hexanediol. hBEX3 assemblies display different morphology in the presence of the tRFs that seems to protect from amyloid formation. Collectively, our findings support a role for tRFs in hBEX3 disorder-to-order transition and modulation of phase transitions. Moreover, hBEX3 aggregation-prone features and the specificity in interaction with tRNA fragments advocate paramount importance toward understanding BEX family involvement in neurodevelopment and cell death.
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http://dx.doi.org/10.1016/j.jmb.2020.02.030DOI Listing
March 2020

Impaired neuronal sodium channels cause intranodal conduction failure and reentrant arrhythmias in human sinoatrial node.

Nat Commun 2020 01 24;11(1):512. Epub 2020 Jan 24.

Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.

Mechanisms for human sinoatrial node (SAN) dysfunction are poorly understood and whether human SAN excitability requires voltage-gated sodium channels (Nav) remains controversial. Here, we report that neuronal (n)Nav blockade and selective nNav1.6 blockade during high-resolution optical mapping in explanted human hearts depress intranodal SAN conduction, which worsens during autonomic stimulation and overdrive suppression to conduction failure. Partial cardiac (c)Nav blockade further impairs automaticity and intranodal conduction, leading to beat-to-beat variability and reentry. Multiple nNav transcripts are higher in SAN vs atria; heterogeneous alterations of several isoforms, specifically nNav1.6, are associated with heart failure and chronic alcohol consumption. In silico simulations of Nav distributions suggest that I is essential for SAN conduction, especially in fibrotic failing hearts. Our results reveal that not only cNav but nNav are also integral for preventing disease-induced failure in human SAN intranodal conduction. Disease-impaired nNav may underlie patient-specific SAN dysfunctions and should be considered to treat arrhythmias.
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http://dx.doi.org/10.1038/s41467-019-14039-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981137PMC
January 2020

Mineralocorticoid Receptor Signaling Contributes to Normal Muscle Repair After Acute Injury.

Front Physiol 2019 25;10:1324. Epub 2019 Oct 25.

Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, United States.

Acute skeletal muscle injury is followed by a temporal response of immune cells, fibroblasts, and muscle progenitor cells within the muscle microenvironment to restore function. These same cell types are repeatedly activated in muscular dystrophy from chronic muscle injury, but eventually, the regenerative portion of the cycle is disrupted and fibrosis replaces degenerated muscle fibers. Mineralocorticoid receptor (MR) antagonist drugs have been demonstrated to increase skeletal muscle function, decrease fibrosis, and directly improve membrane integrity in muscular dystrophy mice, and therefore are being tested clinically. Conditional knockout of MR from muscle fibers in muscular dystrophy mice also improves skeletal muscle function and decreases fibrosis. The mechanism of efficacy likely results from blocking MR signaling by its endogenous agonist aldosterone, being produced at high local levels in regions of muscle damage by infiltrating myeloid cells. Since chronic and acute injuries share the same cellular processes to regenerate muscle, and MR antagonists are clinically used for a wide variety of conditions, it is crucial to define the role of MR signaling in normal muscle repair after injury. In this study, we performed acute injuries using barium chloride injections into muscles both in myofiber MR conditional knockout mice on a wild-type background (MRcko) and in MR antagonist-treated wild-type mice. Steps of the muscle regeneration response were analyzed at 1, 4, 7, or 14 days after injury. Presence of the aldosterone synthase enzyme was also assessed during the injury repair process. We show for the first time aldosterone synthase localization in infiltrating immune cells of normal skeletal muscle after acute injury. MRcko mice had an increased muscle area infiltrated by aldosterone synthase positive myeloid cells compared to control injured animals. Both MRcko and MR antagonist treatment stabilized damaged myofibers and increased collagen infiltration or compaction at 4 days post-injury. MR antagonist treatment also led to reduced myofiber size at 7 and 14 days post-injury. These data support that MR signaling contributes to the normal muscle repair process following acute injury. MR antagonist treatment delays muscle fiber growth, so temporary discontinuation of these drugs after a severe muscle injury could be considered.
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http://dx.doi.org/10.3389/fphys.2019.01324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6830343PMC
October 2019

βIV-Spectrin/STAT3 complex regulates fibroblast phenotype, fibrosis, and cardiac function.

JCI Insight 2019 10 17;4(20). Epub 2019 Oct 17.

The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.

Increased fibrosis is a characteristic remodeling response to biomechanical and neurohumoral stress and a determinant of cardiac mechanical and electrical dysfunction in disease. Stress-induced activation of cardiac fibroblasts (CFs) is a critical step in the fibrotic response, although the precise sequence of events underlying activation of these critical cells in vivo remain unclear. Here, we tested the hypothesis that a βIV-spectrin/STAT3 complex is essential for maintenance of a quiescent phenotype (basal nonactivated state) in CFs. We reported increased fibrosis, decreased cardiac function, and electrical impulse conduction defects in genetic and acquired mouse models of βIV-spectrin deficiency. Loss of βIV-spectrin function promoted STAT3 nuclear accumulation and transcriptional activity, and it altered gene expression and CF activation. Furthermore, we demonstrate that a quiescent phenotype may be restored in βIV-spectrin-deficient fibroblasts by expressing a βIV-spectrin fragment including the STAT3-binding domain or through pharmacological STAT3 inhibition. We found that in vivo STAT3 inhibition abrogates fibrosis and cardiac dysfunction in the setting of global βIV-spectrin deficiency. Finally, we demonstrate that fibroblast-specific deletion of βIV-spectrin is sufficient to induce fibrosis and decreased cardiac function. We propose that the βIV-spectrin/STAT3 complex is a determinant of fibroblast phenotype and fibrosis, with implications for remodeling response in cardiovascular disease (CVD).
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http://dx.doi.org/10.1172/jci.insight.131046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824442PMC
October 2019

IFITM3 protects the heart during influenza virus infection.

Proc Natl Acad Sci U S A 2019 09 26;116(37):18607-18612. Epub 2019 Aug 26.

Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210;

Influenza virus can disseminate from the lungs to the heart in severe infections and can induce cardiac pathology, but this has been difficult to study due to a lack of small animal models. In humans, polymorphisms in the gene encoding the antiviral restriction factor IFN-induced transmembrane protein 3 (IFITM3) are associated with susceptibility to severe influenza, but whether IFITM3 deficiencies contribute to cardiac dysfunction during infection is unclear. We show that IFITM3 deficiency in a new knockout (KO) mouse model increases weight loss and mortality following influenza virus infections. We investigated this enhanced pathogenesis with the A/PR/8/34 (H1N1) (PR8) influenza virus strain, which is lethal in KO mice even at low doses, and observed increased replication of virus in the lungs, spleens, and hearts of KO mice compared with wild-type (WT) mice. Infected IFITM3 KO mice developed aberrant cardiac electrical activity, including decreased heart rate and irregular, arrhythmic RR (interbeat) intervals, whereas WT mice exhibited a mild decrease in heart rate without irregular RR intervals. Cardiac electrical dysfunction in PR8-infected KO mice was accompanied by increased activation of fibrotic pathways and fibrotic lesions in the heart. Infection with a sublethal dose of a less virulent influenza virus strain (A/WSN/33 [H1N1]) resulted in a milder cardiac electrical dysfunction in KO mice that subsided as the mice recovered. Our findings reveal an essential role for IFITM3 in limiting influenza virus replication and pathogenesis in heart tissue and establish IFITM3 KO mice as a powerful model for studying mild and severe influenza virus-induced cardiac dysfunction.
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http://dx.doi.org/10.1073/pnas.1900784116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744864PMC
September 2019

Optimized protocols for isolation, fixation, and flow cytometric characterization of leukocytes in ischemic hearts.

Am J Physiol Heart Circ Physiol 2019 09 2;317(3):H658-H666. Epub 2019 Aug 2.

Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus, Ohio.

Immune activation post-myocardial infarction is an orchestrated sequence of cellular responses to effect tissue repair and healing. However, excessive and dysregulated inflammation can result in left ventricular remodeling and pathological alterations in the structural and mechanical attributes of the heart. Identification of key pathways and critical cellular mediators of inflammation is thus essential to design immunomodulatory therapies for myocardial infarction and ischemic heart failure. Despite this, the experimental approaches to isolate mononuclear cells from the heart are diverse, and detailed protocols to enable maximum yield of live cells in the shortest time possible are not readily available. Here, we describe optimized protocols for the isolation, fixation, and flow cytometric characterization of cardiac CD45 leukocytes. These protocols circumvent time-consuming coronary perfusion and density-mediated cell-separation steps, resulting in high cellular yields from cardiac digests devoid of contaminating intravascular cells. Moreover, in contrast to methanol and acetone, we show that cell fixation using 1% paraformaldehyde is most optimal as it does not affect antibody binding or cellular morphology, thereby providing a considerable advantage to study activation/infiltration-associated changes in cellular granularity and size. These are highly versatile methods that can easily be streamlined for studies requiring simultaneous isolation of immune cells from different tissues or deployment in studies containing a large cohort of samples with time-sensitive constraints. In this article, we describe optimized protocols for the isolation, fixation, and flow cytometric analysis of immune cells from the ischemic/nonischemic hearts. These protocols are optimized to process several samples/tissues, simultaneously enabling maximal yield of immune cells in the shortest time possible. We show that the low-speed centrifugation can be used as an effective alternative to lengthy coronary perfusion to remove intravascular cells, and sieving through 40-μm filter can replace density-mediated mononuclear cell separation which usually results in 50-70% cell loss in the sedimented pellets. We also show that cell fixation using 1% paraformaldehyde is better than the organic solvents such as methanol and acetone for flow cytometric analysis.
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http://dx.doi.org/10.1152/ajpheart.00137.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6766726PMC
September 2019

RNA epigenetics and cardiovascular diseases.

J Mol Cell Cardiol 2019 04 14;129:272-280. Epub 2019 Mar 14.

Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA. Electronic address:

Cardiovascular disease (CVD) remains the leading cause of death in the Western world. Despite advances in the prevention and in the management of CVD, the role of RNA epigenetics in the cardiovascular system has been until recently unexplored. The rapidly expanding research field of RNA modifications has introduced a novel layer of gene regulation in mammalian cells. RNA modifications may control all aspects of RNA metabolism, and their study reveals previously unrecognized regulatory pathways that may determine gene expression at a post-transcriptional level. Understanding the role of RNA modifications in CVD may lead towards a better understanding of disease mechanisms and the development of novel biomarkers or therapeutic strategies. In this review, we highlight the most recent and major reports in the field of RNA methylation and adenosine to inosine RNA editing related to the cardiovascular field and we discuss how this breakthrough will advance the field of precision medicine.
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http://dx.doi.org/10.1016/j.yjmcc.2019.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693324PMC
April 2019

Cardiovascular inflammation: RNA takes the lead.

J Mol Cell Cardiol 2019 04 14;129:247-256. Epub 2019 Mar 14.

Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, United States. Electronic address:

Inflammation has recently gained tremendous attention as a key contributor in several chronic diseases. While physiological inflammation is essential to counter a wide variety of damaging stimuli and to improve wound healing, dysregulated inflammation such as in the myocardium and vasculature can promote cardiovascular diseases. Given the high severity, prevalence, and economic burden of these diseases, understanding the factors involved in the regulation of physiological inflammation is essential. Like other complex biological phenomena, RNA-based processes are emerging as major regulators of inflammatory responses. Among such processes are cis-regulatory elements in the mRNA of inflammatory genes, noncoding RNAs directing the production or localization of inflammatory cytokines/chemokines, or pathogenic RNA driving inflammatory responses. In this review, we describe several specific RNA-based molecular mechanisms by which physiological inflammation pertaining to cardiovascular diseases is regulated. These include the role of AU-rich element-containing mRNAs, long non-coding RNAs, microRNAs, and viral RNAs.
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http://dx.doi.org/10.1016/j.yjmcc.2019.03.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6641543PMC
April 2019

Mineralocorticoid receptor antagonists improve membrane integrity independent of muscle force in muscular dystrophy.

Hum Mol Genet 2019 06;28(12):2030-2045

Department of Physiology and Cell Biology.

Mineralocorticoid receptor (MR) drugs have been used clinically for decades to treat cardiovascular diseases. MR antagonists not only show preclinical efficacy for heart in Duchenne muscular dystrophy (DMD) models but also improve skeletal muscle force and muscle membrane integrity. The mechanisms of action of MR antagonists in skeletal muscles are entirely unknown. Since MR are present in many cell types in the muscle microenvironment, it is critical to define cell-intrinsic functions in each cell type to ultimately optimize antagonist efficacy for use in the widest variety of diseases. We generated a new conditional knockout of MR in myofibers and quantified cell-intrinsic mechanistic effects on functional and histological parameters in a DMD mouse model. Skeletal muscle MR deficiency led to improved respiratory muscle force generation and less deleterious fibrosis but did not reproduce MR antagonist efficacy on membrane susceptibility to induced damage. Surprisingly, acute application of MR antagonist to muscles led to improvements in membrane integrity after injury independent of myofiber MR. These data demonstrate that MR antagonists are efficacious to dystrophic skeletal muscles through both myofiber intrinsic effects on muscle force and downstream fibrosis and extrinsic functions on membrane stability. MR antagonists may therefore be applicable for treating more general muscle weakness and possibly other conditions that result from cell injuries.
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http://dx.doi.org/10.1093/hmg/ddz039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548225PMC
June 2019

The N-Methyladenosine mRNA Methylase METTL3 Controls Cardiac Homeostasis and Hypertrophy.

Circulation 2019 01;139(4):533-545

Department of Physiology and Cell Biology (L.E.D., F.A.), Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus.

Background: N-Methyladenosine (m6A) methylation is the most prevalent internal posttranscriptional modification on mammalian mRNA. The role of m6A mRNA methylation in the heart is not known.

Methods: To determine the role of m6A methylation in the heart, we isolated primary cardiomyocytes and performed m6A immunoprecipitation followed by RNA sequencing. We then generated genetic tools to modulate m6A levels in cardiomyocytes by manipulating the levels of the m6A RNA methylase methyltransferase-like 3 (METTL3) both in culture and in vivo. We generated cardiac-restricted gain- and loss-of-function mouse models to allow assessment of the METTL3-m6A pathway in cardiac homeostasis and function.

Results: We measured the level of m6A methylation on cardiomyocyte mRNA, and found a significant increase in response to hypertrophic stimulation, suggesting a potential role for m6A methylation in the development of cardiomyocyte hypertrophy. Analysis of m6A methylation showed significant enrichment in genes that regulate kinases and intracellular signaling pathways. Inhibition of METTL3 completely abrogated the ability of cardiomyocytes to undergo hypertrophy when stimulated to grow, whereas increased expression of the m6A RNA methylase METTL3 was sufficient to promote cardiomyocyte hypertrophy both in vitro and in vivo. Finally, cardiac-specific METTL3 knockout mice exhibit morphological and functional signs of heart failure with aging and stress, showing the necessity of RNA methylation for the maintenance of cardiac homeostasis.

Conclusions: Our study identified METTL3-mediated methylation of mRNA on N-adenosines as a dynamic modification that is enhanced in response to hypertrophic stimuli and is necessary for a normal hypertrophic response in cardiomyocytes. Enhanced m6A RNA methylation results in compensated cardiac hypertrophy, whereas diminished m6A drives eccentric cardiomyocyte remodeling and dysfunction, highlighting the critical importance of this novel stress-response mechanism in the heart for maintaining normal cardiac function.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.036146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340720PMC
January 2019

Genetic manipulation of CCN2/CTGF unveils cell-specific ECM-remodeling effects in injured skeletal muscle.

FASEB J 2019 02 14;33(2):2047-2057. Epub 2018 Sep 14.

Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA.

In skeletal muscle, extracellular matrix (ECM) remodeling can either support the complete regeneration of injured muscle or facilitate pathologic fibrosis and muscle degeneration. Muscular dystrophy (MD) is a group of genetic disorders that results in a progressive decline in muscle function and is characterized by the abundant deposition of fibrotic tissue. Unlike acute injury, where ECM remodeling is acute and transient, in MD, remodeling persists until fibrosis obstructs the regenerative efforts of diseased muscles. Thus, understanding how ECM is deposited and organized is critical in the context of muscle repair. Connective tissue growth factor (CTGF or CCN2) is a matricellular protein expressed by multiple cell types in response to tissue injury. Although used as a general marker of fibrosis, the cell type-dependent role of CTGF in dystrophic muscle has not been elucidated. To address this question, a conditional Ctgf myofiber and fibroblast-knockout mouse lines were generated and crossed to a dystrophic background. Only myofiber-selective inhibition of CTGF protected δ-sarcoglycan-null ( Sgcd) mice from the dystrophic phenotype, and it did so by affecting collagen organization in a way that allowed for improvements in dystrophic muscle regeneration and function. To confirm that muscle-specific CTGF functions to mediate collagen organization, we generated mice with transgenic muscle-specific overexpression of CTGF. Again, genetic modulation of CTGF in muscle was not sufficient to drive fibrosis, but altered collagen content and organization after injury. Our results show that the myofibers are critical mediators of the deleterious effects associated with CTGF in MD and acutely injured skeletal muscle.-Petrosino, J. M., Leask, A., Accornero, F. Genetic manipulation of CCN2/CTGF unveils cell-specific ECM-remodeling effects in injured skeletal muscle.
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http://dx.doi.org/10.1096/fj.201800622RRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338641PMC
February 2019

CTGF/CCN2 is an autocrine regulator of cardiac fibrosis.

J Mol Cell Cardiol 2018 08 21;121:205-211. Epub 2018 Jul 21.

Department of Physiology & Cell Biology, Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University, Wexner Medical Center, Columbus, OH, USA. Electronic address:

Cardiac fibrosis is a common pathologic consequence of stress insult to the heart and is characterized by abnormal deposition of fibrotic extracellular matrix that compromises cardiac function. Cardiac fibroblasts are key mediators of fibrotic remodeling and are regulated by secreted stress-response proteins. The matricellular protein connective tissue growth factor (CTGF), or CCN2, is strongly produced by injured cardiomyocytes and although it is considered a pro-fibrotic factor in many organ systems, its role in cardiac fibrosis is controversial. Here we adopted a cell-specific genetic approach to conditionally delete CCN2 in either cardiomyocytes or activated fibroblasts. Fibrosis was induced by angiotensin II-based neurohumoral stimulation, an insult that strongly induces CCN2 expression from cardiomyocytes and to a lesser extent in fibroblasts. Remarkably, only CCN2 deletion from activated fibroblasts inhibited the fibrotic remodeling while deletion from cardiomyocytes (the main source of CCN2 in the heart) had no effects. In vitro experiments revealed that although efficiently secreted by both fibroblasts and cardiomyocytes, only fibroblast-derived CCN2 is proficient in its ability to fully activate fibroblasts. These results overall indicate that although secreted into the extracellular matrix, CCN2 acts in an autocrine fashion. Secretion of CCN2 by cardiomyocytes is not pro-fibrotic, while fibroblast-derived CCN2 can modulate fibrosis in the heart. In conclusion we found that cardiomyocyte-derived CCN2 is dispensable for cardiac fibrosis, while inhibiting CCN2 induction in activated fibroblasts is sufficient to abrogate the cardiac fibrotic response to angiotensin II. Hence, CCN2 is an autocrine factor in the heart.
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http://dx.doi.org/10.1016/j.yjmcc.2018.07.130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6260782PMC
August 2018

At the heart of inter- and intracellular signaling: the intercalated disc.

Biophys Rev 2018 Aug 6;10(4):961-971. Epub 2018 Jun 6.

Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA.

Proper cardiac function requires the synchronous mechanical and electrical coupling of individual cardiomyocytes. The intercalated disc (ID) mediates coupling of neighboring myocytes through intercellular signaling. Intercellular communication is highly regulated via intracellular signaling, and signaling pathways originating from the ID control cardiomyocyte remodeling and function. Herein, we present an overview of the inter- and intracellular signaling that occurs at and originates from the intercalated disc in normal physiology and pathophysiology. This review highlights the importance of the intercalated disc as an integrator of signaling events regulating homeostasis and stress responses in the heart and the center of several pathophysiological processes mediating the development of cardiomyopathies.
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http://dx.doi.org/10.1007/s12551-018-0430-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6082301PMC
August 2018

BEX1 is an RNA-dependent mediator of cardiomyopathy.

Nat Commun 2017 11 30;8(1):1875. Epub 2017 Nov 30.

Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.

Regulation of mRNA splicing, processing and stability is increasingly recognized as a critical control point in dynamically altering gene expression during stress or disease. Very little is understood of this process in heart failure. Here, we show that BEX1 is a heart failure-induced gene functioning as an mRNA-associated protein that enhances expression of a subset of cardiac disease-promoting genes. Modeling the increase in BEX1 that occurs in disease, cardiac-specific BEX1 transgenic mice show worse cardiac disease with stress stimulation, whereas Bex1 gene-deleted mice are protected from heart failure-promoting insults. Proteomic and interactive screening assays show that BEX1 is part of a large ribonucleoprotein processing complex involved in regulating proinflammatory mRNA expression in the heart. Specifically, induction of BEX1 augments the stability and expression of AU-rich element containing mRNAs typically found within proinflammatory genes. Thus, BEX1 functions as an mRNA-dependent effector that augments pathology-promoting gene expression during heart failure.
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http://dx.doi.org/10.1038/s41467-017-02005-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5709413PMC
November 2017

TGF-β1 affects cell-cell adhesion in the heart in an NCAM1-dependent mechanism.

J Mol Cell Cardiol 2017 11 1;112:49-57. Epub 2017 Sep 1.

Department of Physiology & Cell Biology, Dorothy M. Davis Heart & Lung Research Institute, Columbus, OH, USA. Electronic address:

The contractile property of the myocardium is maintained by cell-cell junctions enabling cardiomyocytes to work as a syncytium. Alterations in cell-cell junctions are observed in heart failure, a disease characterized by the activation of Transforming Growth Factor beta 1 (TGFβ1). While TGFβ1 has been implicated in diverse biologic responses, its molecular function in controlling cell-cell adhesion in the heart has never been investigated. Cardiac-specific transgenic mice expressing active TGFβ1 were generated to model the observed increase in activity in the failing heart. Activation of TGFβ1 in the heart was sufficient to drive ventricular dysfunction. To begin to understand the function of this important molecule we undertook an extensive structural analysis of the myocardium by electron microscopy and immunostaining. This approach revealed that TGFβ1 alters intercalated disc structures and cell-cell adhesion in ventricular myocytes. Mechanistically, we found that TGFβ1 induces the expression of neural adhesion molecule 1 (NCAM1) in cardiomyocytes in a p38-dependent pathway, and that selective targeting of NCAM1 was sufficient to rescue the cell adhesion defect observed when cardiomyocytes were treated with TGFβ1. Importantly, NCAM1 was upregulated in human heart samples from ischemic and non-ischemic cardiomyopathy patients and NCAM1 protein levels correlated with the degree of TGFβ1 activity in the human cardiac ventricle. Overall, we found that TGFβ1 is deleterious to the heart by regulating the adhesion properties of cardiomyocytes in an NCAM1-dependent mechanism. Our results suggest that inhibiting NCAM1 would be cardioprotective, counteract the pathological action of TGFβ1 and reduce heart failure severity.
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http://dx.doi.org/10.1016/j.yjmcc.2017.08.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5647243PMC
November 2017

Rationally engineered Troponin C modulates in vivo cardiac function and performance in health and disease.

Nat Commun 2016 Feb 24;7:10794. Epub 2016 Feb 24.

Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology, Columbus, Ohio 43210, USA.

Treatment for heart disease, the leading cause of death in the world, has progressed little for several decades. Here we develop a protein engineering approach to directly tune in vivo cardiac contractility by tailoring the ability of the heart to respond to the Ca(2+) signal. Promisingly, our smartly formulated Ca(2+)-sensitizing TnC (L48Q) enhances heart function without any adverse effects that are commonly observed with positive inotropes. In a myocardial infarction (MI) model of heart failure, expression of TnC L48Q before the MI preserves cardiac function and performance. Moreover, expression of TnC L48Q after the MI therapeutically enhances cardiac function and performance, without compromising survival. We demonstrate engineering TnC can specifically and precisely modulate cardiac contractility that when combined with gene therapy can be employed as a therapeutic strategy for heart disease.
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http://dx.doi.org/10.1038/ncomms10794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4770086PMC
February 2016

STIM1 elevation in the heart results in aberrant Ca²⁺ handling and cardiomyopathy.

J Mol Cell Cardiol 2015 Oct 1;87:38-47. Epub 2015 Aug 1.

Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Howard Hughes Medical Institute, Cincinnati, OH, USA. Electronic address:

Stromal interaction molecule 1 (STIM1) is a Ca(2+) sensor that partners with Orai1 to elicit Ca(2+) entry in response to endoplasmic reticulum (ER) Ca(2+) store depletion. While store-operated Ca(2+) entry (SOCE) is important for maintaining ER Ca(2+) homeostasis in non-excitable cells, it is unclear what role it plays in the heart, although STIM1 is expressed in the heart and upregulated during disease. Here we analyzed transgenic mice with STIM1 overexpression in the heart to model the known increase of this protein in response to disease. As expected, STIM1 transgenic myocytes showed enhanced Ca(2+) entry following store depletion and partial co-localization with the type 2 ryanodine receptor (RyR2) within the sarcoplasmic reticulum (SR), as well as enrichment around the sarcolemma. STIM1 transgenic mice exhibited sudden cardiac death as early as 6weeks of age, while mice surviving past 12weeks of age developed heart failure with hypertrophy, induction of the fetal gene program, histopathology and mitochondrial structural alterations, loss of ventricular functional performance and pulmonary edema. Younger, pre-symptomatic STIM1 transgenic mice exhibited enhanced pathology following pressure overload stimulation or neurohumoral agonist infusion, compared to controls. Mechanistically, cardiac myocytes isolated from STIM1 transgenic mice displayed spontaneous Ca(2+) transients that were prevented by the SOCE blocker SKF-96365, increased L-type Ca(2+) channel (LTCC) current, and enhanced Ca(2+) spark frequency. Moreover, adult cardiac myocytes from STIM1 transgenic mice showed both increased diastolic Ca(2+) and maximal transient amplitude but no increase in total SR Ca(2+) load. Associated with this enhanced Ca(2+) profile was an increase in cardiac nuclear factor of activated T-cells (NFAT) and Ca(2+)/calmodulin-dependent kinase II (CaMKII) activity. We conclude that STIM1 has an unexpected function in the heart where it alters communication between the sarcolemma and SR resulting in greater Ca(2+) flux and a leaky SR compartment.
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http://dx.doi.org/10.1016/j.yjmcc.2015.07.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4637225PMC
October 2015

Genetic Analysis of Connective Tissue Growth Factor as an Effector of Transforming Growth Factor β Signaling and Cardiac Remodeling.

Mol Cell Biol 2015 Jun 13;35(12):2154-64. Epub 2015 Apr 13.

Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA Howard Hughes Medical Institute, Cincinnati, Ohio, USA

The matricellular secreted protein connective tissue growth factor (CTGF) is upregulated in response to cardiac injury or with transforming growth factor β (TGF-β) stimulation, where it has been suggested to function as a fibrotic effector. Here we generated transgenic mice with inducible heart-specific CTGF overexpression, mice with heart-specific expression of an activated TGF-β mutant protein, mice with heart-specific deletion of Ctgf, and mice in which Ctgf was also deleted from fibroblasts in the heart. Remarkably, neither gain nor loss of CTGF in the heart affected cardiac pathology and propensity toward early lethality due to TGF-β overactivation in the heart. Also, neither heart-specific Ctgf deletion nor CTGF overexpression altered cardiac remodeling and function with aging or after multiple acute stress stimuli. Cardiac fibrosis was also unchanged by modulation of CTGF levels in the heart with aging, pressure overload, agonist infusion, or TGF-β overexpression. However, CTGF mildly altered the overall cardiac response to TGF-β when pressure overload stimulation was applied. CTGF has been proposed to function as a critical TGF-β effector in underlying tissue remodeling and fibrosis throughout the body, although our results suggest that CTGF is of minimal importance and is an unlikely therapeutic vantage point for the heart.
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http://dx.doi.org/10.1128/MCB.00199-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4438237PMC
June 2015

Myofiber-specific inhibition of TGFβ signaling protects skeletal muscle from injury and dystrophic disease in mice.

Hum Mol Genet 2014 Dec 8;23(25):6903-15. Epub 2014 Aug 8.

Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, 240 Albert Sabin Way, Cincinnati, OH 45229, USA Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, 240 Albert Sabin Way, Cincinnati, OH 45229, USA

Muscular dystrophy (MD) is a disease characterized by skeletal muscle necrosis and the progressive accumulation of fibrotic tissue. While transforming growth factor (TGF)-β has emerged as central effector of MD and fibrotic disease, the cell types in diseased muscle that underlie TGFβ-dependent pathology have not been segregated. Here, we generated transgenic mice with myofiber-specific inhibition of TGFβ signaling owing to expression of a TGFβ type II receptor dominant-negative (dnTGFβRII) truncation mutant. Expression of dnTGFβRII in myofibers mitigated the dystrophic phenotype observed in δ-sarcoglycan-null (Sgcd(-/-)) mice through a mechanism involving reduced myofiber membrane fragility. The dnTGFβRII transgene also reduced muscle injury and improved muscle regeneration after cardiotoxin injury, as well as increased satellite cell numbers and activity. An unbiased global expression analysis revealed a number of potential mechanisms for dnTGFβRII-mediated protection, one of which was induction of the antioxidant protein metallothionein (Mt). Indeed, TGFβ directly inhibited Mt gene expression in vitro, the dnTGFβRII transgene conferred protection against reactive oxygen species accumulation in dystrophic muscle and treatment with Mt mimetics protected skeletal muscle upon injury in vivo and improved the membrane stability of dystrophic myofibers. Hence, our results show that the myofibers are central mediators of the deleterious effects associated with TGFβ signaling in MD.
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http://dx.doi.org/10.1093/hmg/ddu413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4271062PMC
December 2014

Enhanced Ca²⁺ influx from STIM1-Orai1 induces muscle pathology in mouse models of muscular dystrophy.

Hum Mol Genet 2014 Jul 20;23(14):3706-15. Epub 2014 Feb 20.

Department of Pediatrics, University of Cincinnati and Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA and

Muscular dystrophy is a progressive muscle wasting disease that is thought to be initiated by unregulated Ca(2+) influx into myofibers leading to their death. Store-operated Ca(2+) entry (SOCE) through sarcolemmal Ca(2+) selective Orai1 channels in complex with STIM1 in the sarcoplasmic reticulum is one such potential disease mechanism for pathologic Ca(2+) entry. Here, we generated a mouse model of STIM1 overexpression in skeletal muscle to determine whether this type of Ca(2+) entry could induce muscular dystrophy. Myofibers from muscle-specific STIM1 transgenic mice showed a significant increase in SOCE in skeletal muscle, modeling an observed increase in the same current in dystrophic myofibers. Histological and biochemical analysis of STIM1 transgenic mice showed fulminant muscle disease characterized by myofiber necrosis, swollen mitochondria, infiltration of inflammatory cells, enhanced interstitial fibrosis and elevated serum creatine kinase levels. This dystrophic-like disease in STIM1 transgenic mice was abrogated by crossing in a transgene expressing a dominant-negative Orai1 (dnOrai1) mutant. The dnOrai1 transgene also significantly reduced the severity of muscular dystrophy in both mdx (dystrophin mutant mice) and δ-sarcoglycan-deficient (Sgcd(-/-)) mouse models of disease. Hence, Ca(2+) influx across an unstable sarcolemma due to increased activity of a STIM1-Orai1 complex is a disease determinant in muscular dystrophy, and hence, SOCE represents a potential therapeutic target.
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http://dx.doi.org/10.1093/hmg/ddu079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4065147PMC
July 2014

Unrestrained p38 MAPK activation in Dusp1/4 double-null mice induces cardiomyopathy.

Circ Res 2013 Jan 19;112(1):48-56. Epub 2012 Sep 19.

Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.

Rationale: Mitogen-activated protein kinases (MAPKs) are activated in the heart by disease-inducing and stress-inducing stimuli, where they participate in hypertrophy, remodeling, contractility, and heart failure. A family of dual-specificity phosphatases (DUSPs) directly inactivates each of the MAPK terminal effectors, potentially serving a cardioprotective role.

Objective: To determine the role of DUSP1 and DUSP4 in regulating p38 MAPK function in the heart and the effect on disease.

Methods And Results: Here, we generated mice and mouse embryonic fibroblasts lacking both Dusp1 and Dusp4 genes. Although single nulls showed no molecular effects, combined disruption of Dusp1/4 promoted unrestrained p38 MAPK activity in both mouse embryonic fibroblasts and the heart, with no change in the phosphorylation of c-Jun N-terminal kinases or extracellular signal-regulated kinases at baseline or with stress stimulation. Single disruption of either Dusp1 or Dusp4 did not result in cardiac pathology, although Dusp1/4 double-null mice exhibited cardiomyopathy and increased mortality with aging. Pharmacological inhibition of p38 MAPK with SB731445 ameliorated cardiomyopathy in Dusp1/4 double-null mice, indicating that DUSP1/4 function primarily through p38 MAPK in affecting disease. At the cellular level, unrestrained p38 MAPK activity diminished cardiac contractility and Ca2+ handling, which was acutely reversed with a p38 inhibitory compound. Poor function in Dusp1/4 double-null mice also was partially rescued by phospholamban deletion.

Conclusions: Our data demonstrate that Dusp1 and Dusp4 are cardioprotective genes that play a critical role in the heart by dampening p38 MAPK signaling that would otherwise reduce contractility and induce cardiomyopathy.
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http://dx.doi.org/10.1161/CIRCRESAHA.112.272963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5929162PMC
January 2013

Placental growth factor as a protective paracrine effector in the heart.

Trends Cardiovasc Med 2011 Nov;21(8):220-4

Department of Pediatrics, Division of Molecular Cardiovascular Biology and the Howard Hughes Medical Institute, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.

In response to injury, the myocardium hypertrophies in an attempt to maintain or augment function, which is associated with ventricular remodeling and changes in capillary density. During the compensatory phase of the hypertrophic response, the myocardium maintains output and is characterized by a coordinated neo-angiogenic and fibrotic response that supports cardiomyocyte health and survival. Emerging evidence shows that paracrine-mediated cross talk between cardiac myocytes and nonmyocytes within the heart is critical for cardiac adaptation to stress, including the extent of hypertrophy and angiogenesis. This review discusses recent results indicating that placental growth factor (PGF; also called PlGF), a secreted factor within the vascular endothelial growth factor superfamily, is a pivotal mediator of adaptive cardiac hypertrophy and beneficial angiogenesis through its ability to coordinate the intercellular communication between different cell types in the heart.
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http://dx.doi.org/10.1016/j.tcm.2012.05.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3424519PMC
November 2011

Placental growth factor regulates cardiac adaptation and hypertrophy through a paracrine mechanism.

Circ Res 2011 Jul 2;109(3):272-80. Epub 2011 Jun 2.

Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, 240 Albert Sabin Way, Cincinnati, OH 45229, USA.

Rationale: Paracrine growth factor-mediated crosstalk between cardiac myocytes and nonmyocytes in the heart is critical for programming adaptive cardiac hypertrophy in which myocyte size, capillary density, and the extracellular matrix function coordinately.

Objective: To examine the role that placental growth factor (PGF) plays in the heart as a paracrine regulator of cardiac adaptation to stress stimulation.

Methods And Results: PGF is induced in the heart after pressure-overload stimulation, where it is expressed in both myocytes and nonmyocytes. We generated cardiac-specific and adult inducible PGF-overexpressing transgenic mice and analyzed Pgf(-/-) mice to examine the role that this factor plays in cardiac disease and paracrine signaling. Although PGF transgenic mice did not have a baseline phenotype or a change in capillary density, they did exhibit a greater cardiac hypertrophic response, a greater increase in capillary density, and increased fibroblast content in the heart in response to pressure-overload stimulation. PGF transgenic mice showed a more adaptive type of cardiac growth that was protective against signs of failure with pressure overload and neuroendocrine stimulation. Antithetically, Pgf(-/-) mice rapidly died of heart failure within 1 week of pressure overload, they showed an inability to upregulate angiogenesis, and they showed significantly less fibroblast activity in the heart. Mechanistically, we show that PGF does not have a direct effect on cardiomyocytes but works through endothelial cells and fibroblasts by inducing capillary growth and fibroblast proliferation, which secondarily support greater cardiac hypertrophy through intermediate paracrine growth factors such as interleukin-6.

Conclusions: PGF is a secreted factor that supports hypertrophy and cardiac function during pressure overload by affecting endothelial cells and fibroblasts that in turn stimulate and support the myocytes through additional paracrine factors.
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http://dx.doi.org/10.1161/CIRCRESAHA.111.240820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3146170PMC
July 2011