Vascular Aging from DNA Damage to Protection

Aging is highly associated with development of cardiovascular disease; however, the underlying mechanisms of these processes are not well understood. Recent advancements in aging research underscore the im

The effect of the thioether-bridged, stabilized angiotensin-(1-7) analogue cyclic Ang-(1-7) on cardiac remodeling and endothelial function in rats with myocardial infarction

Modulation of renin-angiotensin system (RAS) by angiotensin-(17) (Ang-(17)) is an attractive approach to combat the detrimental consequences of myocardial infarction (MI). However Ang-(17) has limited clinical potential due to its unfavorable pharmacokinetic profile. We investigated effects of a stabilized, thioether-bridged analogue of Ang-(17) called cyclic Ang-(17) in rat model of myocardial infarction. Rats underwent coronary ligation or sham surgery. Two weeks thereafter infusion with 0.24 or 2.4 μg/kg/h cAng-(17) or saline was started for 8 weeks. Thereafter, cardiac morphometric and hemodynamic variables as wells as aortic endothelial function were measured. The average infarct size was 13.8 and was not changed by cAng-(17) treatment. MI increased heart weight and myocyte size, which was restored by cAng-(17) to sham levels. In addition, cAng-(17) lowered left ventricular end-diastolic pressure and improved endothelial function. The results suggest that cAng-(17) is a promising new agent in treatment of myocardial infarction and warrant further research.</p

The Effect of the Thioether-Bridged, Stabilized Angiotensin-(1–7) Analogue Cyclic Ang-(1–7) on Cardiac Remodeling and Endothelial Function in Rats with Myocardial Infarction

Modulation of renin-angiotensin system (RAS) by angiotensin-(1–7) (Ang-(1–7)) is an attractive approach to combat the detrimental consequences of myocardial infarction (MI). However Ang-(1–7) has limited clinical potential due to its unfavorable pharmacokinetic profile. We investigated effects of a stabilized, thioether-bridged analogue of Ang-(1–7) called cyclic Ang-(1–7) in rat model of myocardial infarction. Rats underwent coronary ligation or sham surgery. Two weeks thereafter infusion with 0.24 or 2.4 μg/kg/h cAng-(1–7) or saline was started for 8 weeks. Thereafter, cardiac morphometric and hemodynamic variables as wells as aortic endothelial function were measured. The average infarct size was 13.8% and was not changed by cAng-(1–7) treatment. MI increased heart weight and myocyte size, which was restored by cAng-(1–7) to sham levels. In addition, cAng-(1–7) lowered left ventricular end-diastolic pressure and improved endothelial function. The results suggest that cAng-(1–7) is a promising new agent in treatment of myocardial infarction and warrant further research

The renin-angiotensin system, bone marrow and progenitor cells

Modulation of the RAS (renin-angiotensin system), in particular of the function of the hormones AngII (angiotensin II) and Ang-(1-7) [angiotensin-(1-7)], is an important target for pharmacotherapy in the cardiovascular system. In the classical view, such modulation affects cardiovascular cells to decrease hypertrophy, fibrosis and endothelial dysfunction, and improves diuresis. In this view, excessive stimulation of AT(1) receptors (AngII type 1 receptors) fulfils a detrimental role, as it promotes cardiovascular pathogenesis, and this is opposed by stimulation of the AT(2) receptor (angiotensin II type 2 receptor) and the Ang-(1-7) receptor encoded by the Mas proto-oncogene. In recent years, this view has been broadened with the observation that the RAS regulates bone marrow stromal cells and stem cells, thus involving haematopoiesis and tissue regeneration by progenitor cells. This change of paradigm has enlarged the field of perspectives for therapeutic application of existing as well as newly developed medicines that alter angiotensin signalling, which now stretches beyond cardiovascular therapy. In the present article, we review the role of Angll and Ang-(1-7) and their respective receptors in haematopoietic and mesenchymal stem cells, and discuss possible pharmacotherapeutical implications

The renin-angiotensin system, bone marrow and progenitor cells

Modulation of the RAS (renin-angiotensin system), in particular of the function of the hormones AngII (angiotensin II) and Ang-(1-7) [angiotensin-(1-7)], is an important target for pharmacotherapy in the cardiovascular system. In the classical view, such modulation affects cardiovascular cells to decrease hypertrophy, fibrosis and endothelial dysfunction, and improves diuresis. In this view, excessive stimulation of AT1 receptors (AngII type 1 receptors) fulfils a detrimental role, as it promotes cardiovascular pathogenesis, and this is opposed by stimulation of the AT2 receptor (angiotensin II type 2 receptor) and the Ang-(1-7) receptor encoded by the Mas proto-oncogene. In recent years, this view has been broadened with the observation that the RAS regulates bone marrow stromal cells and stem cells, thus involving haematopoiesis and tissue regeneration by progenitor cells. This change of paradigm has enlarged the field of perspectives for therapeutic application of existing as well as newly developed medicines that alter angiotensin signalling, which now stretches beyond cardiovascular therapy. In the present article, we review the role of AngII and Ang-(1-7) and their respective receptors in haematopoietic and mesenchymal stem cells, and discuss possible pharmacotherapeutical implications

Cell cycle gene regulation dynamics revealed by RNA velocity and deep-learning

International audienceAbstract Despite the fact that the cell cycle is a fundamental process of life, a detailed quantitative understanding of gene regulation dynamics throughout the cell cycle is far from complete. Single-cell RNA-sequencing (scRNA-seq) technology gives access to these dynamics without externally perturbing the cell. Here, by generating scRNA-seq libraries in different cell systems, we observe cycling patterns in the unspliced-spliced RNA space of cell cycle-related genes. Since existing methods to analyze scRNA-seq are not efficient to measure cycling gene dynamics, we propose a deep learning approach (DeepCycle) to fit these patterns and build a high-resolution map of the entire cell cycle transcriptome. Characterizing the cell cycle in embryonic and somatic cells, we identify major waves of transcription during the G1 phase and systematically study the stages of the cell cycle. Our work will facilitate the study of the cell cycle in multiple cellular models and different biological contexts

Histone H2Bub1 deubiquitylation is essential for mouse development, but does not regulate global RNA polymerase II transcription

International audienceAbstract Co-activator complexes dynamically deposit post-translational modifications (PTMs) on histones, or remove them, to regulate chromatin accessibility and/or to create/erase docking surfaces for proteins that recognize histone PTMs. SAGA (Spt-Ada-Gcn5 Acetyltransferase) is an evolutionary conserved multisubunit co-activator complex with modular organization. The deubiquitylation module (DUB) of mammalian SAGA complex is composed of the ubiquitin-specific protease 22 (USP22) and three adaptor proteins, ATXN7, ATXN7L3 and ENY2, which are all needed for the full activity of the USP22 enzyme to remove monoubiquitin (ub1) from histone H2B. Two additional USP22-related ubiquitin hydrolases (called USP27X or USP51) have been described to form alternative DUBs with ATXN7L3 and ENY2, which can also deubiquitylate H2Bub1. Here we report that USP22 and ATXN7L3 are essential for normal embryonic development of mice, however their requirements are not identical during this process, as Atxn7l3 −/− embryos show developmental delay already at embryonic day (E) 7.5, while Usp22 −/− embryos are normal at this stage, but die at E14.5. Global histone H2Bub1 levels were only slightly affected in Usp22 null embryos, in contrast H2Bub1 levels were strongly increased in Atxn7l3 null embryos and derived cell lines. Our transcriptomic analyses carried out from wild type and Atxn7l3 −/− mouse embryonic stem cells (mESCs), or primary mouse embryonic fibroblasts (MEFs) suggest that the ATXN7L3-related DUB activity regulates only a subset of genes in both cell types. However, the gene sets and the extent of their deregulation were different in mESCs and MEFs. Interestingly, the strong increase of H2Bub1 levels observed in the Atxn7l3 −/− mESCs, or Atxn7l3 −/− MEFs, does not correlate with the modest changes in RNA Polymerase II (Pol II) occupancy and lack of changes in Pol II elongation observed in the two Atxn7l3 −/− cellular systems. These observations together indicate that deubiquitylation of histone H2Bub1 does not directly regulate global Pol II transcription elongation

Compound 21 Induces Vasorelaxation via an Endothelium- and Angiotensin II Type 2 Receptor-Independent Mechanism

Angiotensin II type 2 (AT(2)) receptor stimulation has been linked to vasodilation. Yet, AT(2) receptor-independent hypertension and hypotension (or no effect on blood pressure) have been observed in vivo after application of the AT(2) receptor agonist compound 21 (C21). We, therefore, studied its effects in vitro, using preparations known to display AT(2) receptor-mediated responses. Hearts of Wistar rats, spontaneously hypertensive rats (SHRs), C57Bl/6 mice, and AT(2) receptor knockout mice were perfused according to Langendorff. Mesenteric and iliac arteries of these animals, as well as coronary microarteries from human donor hearts, were mounted in Mulvany myographs. In the coronary vascular bed of Wistar rats, C57Bl/6 mice, and AT(2) receptor knockout mice, C21 induced constriction followed by dilation. SHR hearts displayed enhanced constriction and no dilation. Irbesartan (angiotensin II type 1 receptor blocker) abolished the constriction and enhanced or (in SHRs) reintroduced dilation, and PD123319 (AT(2) receptor blocker) did not block the latter. C21 relaxed preconstricted vessels of all species, and this did not depend on angiotensin II receptors, the endothelium, or the NO-guanylyl cyclase-cGMP pathway. C21 constricted SHR iliac arteries but none of the other vessels, and irbesartan prevented this. C21 shifted the concentration-response curves to U46619 (thromboxane A(2) analog) and phenylephrine (alpha-adrenoceptor agonist) but not ionomycine (calcium ionophore) to the right. In conclusion, C21 did not cause AT(2) receptor-mediated vasodilation. Yet, it did induce vasodilation by blocking calcium transport into the cell and constriction via angiotensin II type 1 receptor stimulation. The latter effect is enhanced in SHRs. These data may explain the varying effects of C21 on blood pressure in vivo. (Hypertension. 2012; 60: 722-729.

The senotherapeutic drug ABT-737 disrupts aberrant p21 expression to restore liver regeneration in adult mice

International audienceYoung mammals possess a limited regenerative capacity in some tissues, which is lost upon maturation. We investigated whether cellular senescence might play a role in such loss during liver regeneration. We found that following partial hepatectomy, the senescence-associated genes p21, p16 Ink4a , and p19 Arf become dynamically expressed in different cell types when regenerative capacity decreases, but without a full senescent response. However, we show that treatment with a senescence-inhibiting drug improves regeneration, by disrupting aberrantly prolonged p21 expression. This work suggests that senescence may initially develop from heterogeneous cellular responses, and that senotherapeutic drugs might be useful in promoting organ regeneration