Clinical and mutational features of three Chinese children with congenital generalized lipodystrophy

Objective: To investigate the clinical and molecular features of congenital generalized lipodystrophy (CGL) in three Chinese patients with various typical manifestations. Methods: Data on clinical symptoms, results of laboratory analyses, and previous treatments in three Chinese patients were collected by a retrospective review of medical records. All coding regions and adjacent exon–intron junction regions of AGPAT2 and BSCL2 genes were amplified by polymerase chain reaction and sequenced.Results: Generalized lipodystrophy, acanthosis nigricans, muscular hypertrophy, severe hypertriglyceridemia, and hepatomegaly were features in all three patients. Patient 1 developed diabetes mellitus at the early age of 2 months and he was the youngest CGL patient reported with overt diabetes. Patient 2 was found to have cardiomyopathy when she was aged 6 months. All of the patients were found to have mutations in the BSCL2 gene, but none of these was a novel mutation. We did not find any AGPAT2 mutation in our patients.Conclusion: All of our patients exhibited characteristic features of CGL due to mutations in the BSCL2 gene

Vezf1 regulates cardiac structure and contractile function

Background Vascular endothelial zinc finger 1 (Vezf1) is a transcription factor previously shown to regulate vasculogenesis and angiogenesis. We aimed to investigate the role of Vezf1 in the postnatal heart. Methods The role of Vezf1 in regulating cardiac growth and contractile function was studied in zebrafish and in primary cardiomyocytes. Findings We find that expression of Vezf1 is decreased in diseased human myocardium and mouse hearts. Our experimental data shows that knockdown of zebrafish Vezf1 reduces cardiac growth and results in impaired ventricular contractile response to β-adrenergic stimuli. However, Vezf1 knockdown is not associated with dysregulation of cardiomyocyte Ca2+ transient kinetics. Gene ontology enrichment analysis indicates that Vezf1 regulates cardiac muscle contraction and dilated cardiomyopathy related genes and we identify cardiomyocyte Myh7/β-MHC as key target for Vezf1. We further identify a key role for an MCAT binding site in the Myh7 promoter regulating the response to Vezf1 knockdown and show that TEAD-1 is a binding partner of Vezf1. Interpretation We demonstrate a role for Vezf1 in regulation of compensatory cardiac growth and cardiomyocyte contractile function, which may be relevant in human cardiac disease.Peer reviewe

Systemic Blockade of ACVR2B Ligands Protects Myocardium from Acute Ischemia-Reperfusion Injury

Activin A and myostatin, members of the transforming growth factor (TGF)-b superfamily of secreted factors, are potent negative regulators of muscle growth, but their contribution to myocardial ischemia-reperfusion (IR) injury is not known. The aim of this study was to investigate if activin 2B (ACVR2B) receptor ligands contribute to myocardial IR injury. Mice were treated with soluble ACVR2B decoy receptor (ACVR2B-Fc) and subjected to myocardial ischemia followed by reperfusion for 6 or 24 h. Systemic blockade of ACVR2B ligands by ACVR2B-Fc was protective against cardiac IR injury, as evidenced by reduced infarcted area, apoptosis, and autophagy and better preserved LV systolic function following IR. ACVR2B-Fc modified cardiac metabolism, LV mitochondrial respiration, as well as cardiac phenotype toward physiological hypertrophy. Similar to its protective role in IR injury in vivo, ACVR2B-Fc antagonized SMAD2 signaling and cell death in cardiomyocytes that were subjected to hypoxic stress. ACVR2B ligand myostatin was found to exacerbate hypoxic stress. In addition to acute cardioprotection in ischemia, ACVR2B-Fc provided beneficial effects on cardiac function in prolonged cardiac stress in cardiotoxicity model. By blocking myostatin, ACVR2B-Fc potentially reduces cardiomyocyte death and modifies cardiomyocyte metabolism for hypoxic conditions to protect the heart from IR injury.Peer reviewe

MiR-185-5p regulates the development of myocardial fibrosis

Background: Cardiac fibrosis stiffens the ventricular wall, predisposes to cardiac arrhythmias and contributes to the development of heart failure. In the present study, our aim was to identify novel miRNAs that regulate the development of cardiac fibrosis and could serve as potential therapeutic targets for myocardial fibrosis. Methods and results: Analysis for cardiac samples from sudden cardiac death victims with extensive myocardial fibrosis as the primary cause of death identified dysregulation of miR-185-5p. Analysis of resident cardiac cells from mice subjected to experimental cardiac fibrosis model showed induction of miR-185-5p expression specifically in cardiac fibroblasts. In vitro, augmenting miR-185-5p induced collagen production and profibrotic activation in cardiac fibroblasts, whereas inhibition of miR-185-5p attenuated collagen production. In vivo, targeting miR-185-5p in mice abolished pressure overload induced cardiac interstitial fibrosis. Mechanistically, miR-185-5p targets apelin receptor and inhibits the anti-fibrotic effects of apelin. Finally, analysis of left ventricular tissue from patients with severe cardiomyopathy showed an increase in miR-185-5p expression together with pro-fibrotic TGF-beta 1 and collagen I. Conclusions: Our data show that miR-185-5p targets apelin receptor and promotes myocardial fibrosis.Peer reviewe

Regulatory Mechanisms of Mitochondrial Function and Cardiac Aging

Aging is a major risk factor for cardiovascular diseases (CVDs), the major cause of death worldwide. Cardiac myocytes, which hold the most abundant mitochondrial population, are terminally differentiated cells with diminished regenerative capacity in the adult. Cardiomyocyte mitochondrial dysfunction is a characteristic feature of the aging heart and one out of the nine features of cellular aging. Aging and cardiac pathologies are also associated with increased senescence in the heart. However, the cause and consequences of cardiac senescence during aging or in cardiac pathologies are mostly unrecognized. Further, despite recent advancement in anti-senescence therapy, the targeted cell type and the effect on cardiac structure and function have been largely overlooked. The unique cellular composition of the heart, and especially the functional properties of cardiomyocytes, need to be considered when designing therapeutics to target cardiac aging. Here we review recent findings regarding key factors regulating cell senescence, mitochondrial health as well as cardiomyocyte rejuvenation

Regulatory mechanisms of mitochondrial function and cardiac aging

Abstract Aging is a major risk factor for cardiovascular diseases (CVDs), the major cause of death worldwide. Cardiac myocytes, which hold the most abundant mitochondrial population, are terminally differentiated cells with diminished regenerative capacity in the adult. Cardiomyocyte mitochondrial dysfunction is a characteristic feature of the aging heart and one out of the nine features of cellular aging. Aging and cardiac pathologies are also associated with increased senescence in the heart. However, the cause and consequences of cardiac senescence during aging or in cardiac pathologies are mostly unrecognized. Further, despite recent advancement in anti-senescence therapy, the targeted cell type and the effect on cardiac structure and function have been largely overlooked. The unique cellular composition of the heart, and especially the functional properties of cardiomyocytes, need to be considered when designing therapeutics to target cardiac aging. Here we review recent findings regarding key factors regulating cell senescence, mitochondrial health as well as cardiomyocyte rejuvenation

Connective Tissue Growth Factor Inhibition Enhances Cardiac Repair and Limits Fibrosis After Myocardial Infarction

Peer reviewe

Controllable Technology for Thermal Expansion Coefficient of Commercial Materials for Solid Oxide Electrolytic Cells

Solid oxide electrolysis cell (SOEC) industrialization has been developing for many years. Commercial materials such as 8 mol% Y2O3-stabilized zirconia (YSZ), Gd0.1Ce0.9O1.95 (GDC), La0.6Sr0.4Co0.2Fe0.8O3−δ (LSCF), La0.6Sr0.4CoO3−δ (LSC), etc., have been used for many years, but the problem of mismatched thermal expansion coefficients of various materials between cells has not been fundamentally solved, which affects the lifetime of SOECs and restricts their industry development. Currently, various solutions have been reported, such as element doping, manufacturing defects, and introducing negative thermal expansion coefficient materials. To promote the development of the SOEC industry, a direct treatment method for commercial materials—quenching and doping—is reported to achieve the controllable preparation of the thermal expansion coefficient of commercial materials. The quenching process only involves the micro-treatment of raw materials and does not have any negative impact on preparation processes such as powder slurry and sintering. It is a simple, low-cost, and universal research strategy to achieve the controllable preparation of the thermal expansion coefficient of the commercial material La0.6Sr0.4Co0.2Fe0.8O3−δ (LSCF) through a quenching process by doping elements and increasing oxygen vacancies in the material. Commercial LSCF materials are heated to 800 °C in a muffle furnace, quickly removed, and cooled and quenched in 3.4 mol/L of prepared Y(NO3)3. The thermal expansion coefficient of the treated material can be reduced to 13.6 × 10−6 K−1, and the blank sample is 14.1 × 10−6 K−1. In the future, it may be possible to use the quenching process to select appropriate doping elements in order to achieve similar thermal expansion coefficients in SOECs