Angiotensin-(1-7) receptor Mas deficiency does not exacerbate cardiac atrophy following high-level spinal cord injury in mice

Experimental spinal cord injury (SCI) causes a morphological and functional deterioration of the heart, in which the renin–angiotensin system (RAS) might play a role. The recently discovered non-canonical axis of RAS with angiotensin-(1-7) and its receptor Mas, which is associated with cardioprotection could be essential to prevent damage to the heart following SCI. We investigated the cardiac consequences of SCI and the role of Mas in female wild-type (WT, n = 22) and mice deficient of Mas (Mas(-/-), n = 25) which underwent spinal cord transection at thoracic level T4 (T4-Tx) or sham-operation by echocardiography (0, 7, 21, and 28 days post-SCI), histology and gene expression analysis at 1 or 2 months post-SCI. We found left ventricular mass reduction with preserved ejection fraction (EF) and fractional shortening in WT as well as Mas(-/-) mice. Cardiac output was reduced in Mas(-/-) mice, whereas stroke volume (SV) was reduced in WT T4-Tx mice. Echocardiographic indices did not differ between the genotypes. Smaller heart weight (HW) and smaller cardiomyocyte diameter at 1 month post-SCI compared to sham mice was independent of genotype. The muscle-specific E3 ubiquitin ligases Atrogin-1/MAFbx and MuRF1 were upregulated or showed a trend for upregulation in WT mice at 2 months post-SCI, respectively. Angiotensinogen gene expression was upregulated at 1 month post-SCI and angiotensin II receptor type 2 downregulated at 2 month post-SCI in Mas(-/-) mice. Mas was downregulated post-SCI. Cardiac atrophy following SCI, not exacerbated by lack of Mas, is a physiological reaction as there were no signs of cardiac pathology and dysfunction

Angiotensin‐II receptor type Ia does not contribute to cardiac atrophy following high‐thoracic spinal cord injury in mice

NEW FINDINGS: What is the central question of this study? Spinal cord injury leads to cardiac atrophy and the role of the renin-angiotensin system with angiotensin II acting via its receptor AT1a in this effect has not been previously explored. What is the main finding and its importance? In mice undergone thoracic level 4 transection, we confirm cardiac atrophy. Knockout of AT1a does not protect mice from cardiac atrophy. We observed no histopathological signs but reduced load-dependent left ventricular function (lower stroke volume and cardiac output) with preserved ejection fraction. Further investigations are warranted to assess cardiac function under stress conditions. ABSTRACT: Spinal cord injury (SCI) leads to cardiac atrophy often accompanied by functional deficits. The renin-angiotensin system (RAS) with angiotensin II (AngII) signalling via its receptor AT1a might contribute to cardiac atrophy post-SCI. We performed spinal cord transection at thoracic level T4 (T4-Tx) or sham-operation in female wild type mice (WT, n = 27) and mice deficient of AT1a (Agtr1a(-/-), n = 27). Echocardiography (0, 7, 21 and 28 days post-SCI) as well as histology and gene expression analyses at 1 and 2 months post-SCI were performed. We found cardiac atrophy post-SCI: reduced heart weight, estimated left ventricular mass in Agtr1a(-/-), and cardiomyocyte diameter in WT mice. Although, the latter as well as stroke volume (SV) and cardiac output (CO) were reduced in Agtr1a(-/-) mice already at baseline, cardiomyocyte diameter was even smaller in injured Agtr1a(-/-) mice compared to injured WT mice. SV and CO were reduced in WT mice post-SCI. Ejection fraction and fractional shortening was preserved post-SCI in both genotypes. There were no histological signs of fibrosis and pathology in the cardiac sections of both genotypes post-SCI. Gene expression of Agtr1a showed a trend for upregulation at 2 months post-SCI, angiotensinogen was upregulated at 2 month post-SCI in both genotypes. AngII receptor type 2 (Agtr2) was up-and down-regulated at 1 and 2 months post-SCI in WT mice, respectively, and Ang-(1-7) receptor (Mas) at 1 and 2 months post-SCI. Atrogin-1/MAFbx and MuRF1, the atrophy markers were not significantly upregulated post-SCI. Our data shows that lack of AT1a does not protect from cardiac atrophy post-SCI

Decreased Rate of Evolution in Y Chromosome STR Loci of Increased Size of the Repeat Unit

Polymorphic Y chromosome short tandem repeats (STRs) have been widely used in population genetic and evolutionary studies. Compared to di-, tri-, and tetranucleotide repeats, STRs with longer repeat units occur more rarely and are far less commonly used.In order to study the evolutionary dynamics of STRs according to repeat unit size, we analysed variation at 24 Y chromosome repeat loci: 1 tri-, 14 tetra-, 7 penta-, and 2 hexanucleotide loci. According to our results, penta- and hexanucleotide repeats have approximately two times lower repeat variance and diversity than tri- and tetranucleotide repeats, indicating that their mutation rate is about half of that of tri- and tetranucleotide repeats. Thus, STR markers with longer repeat units are more robust in distinguishing Y chromosome haplogroups and, in some cases, phylogenetic splits within established haplogroups.Our findings suggest that Y chromosome STRs of increased repeat unit size have a lower rate of evolution, which has significant relevance in population genetic and evolutionary studies

Ethnic Minority–Majority Unions in Estonia

Ethnic minority–majority unions—also referred to as mixed ethnic unions—are often seen as the ultimate evidence of the integration of ethnic minorities into their host societies. We investigated minority–majority unions in Estonia, where ethnic minorities account for one-third of the total population (Russians 26%, followed by Ukrainians, Byelorussians, Finns and other smaller groups). Using data from the 2000 Estonian census and regression models, we found that Slavic women are less likely to be in minority–majority unions than are members of other minority groups, with Russians being the least likely. Finns, who are culturally most similar to the Estonian majority population, are the most likely to form a union with an Estonian. For ethnic minority women, the likelihood of being in minority–majority unions is highest in rural areas and increases over generations, with third-generation immigrants being the most likely. Estonian women are most likely to have a minority partner when they or their parents were born abroad and when they live in urban areas. Our findings suggest that both the opportunity to meet potential partners and openness to other ethnic groups are important factors for understanding the dynamics of minority–majority unions

Genomic analyses inform on migration events during the peopling of Eurasia.

High-coverage whole-genome sequence studies have so far focused on a limited number of geographically restricted populations, or been targeted at specific diseases, such as cancer. Nevertheless, the availability of high-resolution genomic data has led to the development of new methodologies for inferring population history and refuelled the debate on the mutation rate in humans. Here we present the Estonian Biocentre Human Genome Diversity Panel (EGDP), a dataset of 483 high-coverage human genomes from 148 populations worldwide, including 379 new genomes from 125 populations, which we group into diversity and selection sets. We analyse this dataset to refine estimates of continent-wide patterns of heterozygosity, long- and short-distance gene flow, archaic admixture, and changes in effective population size through time as well as for signals of positive or balancing selection. We find a genetic signature in present-day Papuans that suggests that at least 2% of their genome originates from an early and largely extinct expansion of anatomically modern humans (AMHs) out of Africa. Together with evidence from the western Asian fossil record, and admixture between AMHs and Neanderthals predating the main Eurasian expansion, our results contribute to the mounting evidence for the presence of AMHs out of Africa earlier than 75,000 years ago.Support was provided by: Estonian Research Infrastructure Roadmap grant no 3.2.0304.11-0312; Australian Research Council Discovery grants (DP110102635 and DP140101405) (D.M.L., M.W. and E.W.); Danish National Research Foundation; the Lundbeck Foundation and KU2016 (E.W.); ERC Starting Investigator grant (FP7 - 261213) (T.K.); Estonian Research Council grant PUT766 (G.C. and M.K.); EU European Regional Development Fund through the Centre of Excellence in Genomics to Estonian Biocentre (R.V.; M.Me. and A.Me.), and Centre of Excellence for Genomics and Translational Medicine Project No. 2014-2020.4.01.15-0012 to EGC of UT (A.Me.) and EBC (M.Me.); Estonian Institutional Research grant IUT24-1 (L.S., M.J., A.K., B.Y., K.T., C.B.M., Le.S., H.Sa., S.L., D.M.B., E.M., R.V., G.H., M.K., G.C., T.K. and M.Me.) and IUT20-60 (A.Me.); French Ministry of Foreign and European Affairs and French ANR grant number ANR-14-CE31-0013-01 (F.-X.R.); Gates Cambridge Trust Funding (E.J.); ICG SB RAS (No. VI.58.1.1) (D.V.L.); Leverhulme Programme grant no. RP2011-R-045 (A.B.M., P.G. and M.G.T.); Ministry of Education and Science of Russia; Project 6.656.2014/K (S.A.F.); NEFREX grant funded by the European Union (People Marie Curie Actions; International Research Staff Exchange Scheme; call FP7-PEOPLE-2012-IRSES-number 318979) (M.Me., G.H. and M.K.); NIH grants 5DP1ES022577 05, 1R01DK104339-01, and 1R01GM113657-01 (S.Tis.); Russian Foundation for Basic Research (grant N 14-06-00180a) (M.G.); Russian Foundation for Basic Research; grant 16-04-00890 (O.B. and E.B); Russian Science Foundation grant 14-14-00827 (O.B.); The Russian Foundation for Basic Research (14-04-00725-a), The Russian Humanitarian Scientific Foundation (13-11-02014) and the Program of the Basic Research of the RAS Presidium “Biological diversity” (E.K.K.); Wellcome Trust and Royal Society grant WT104125AIA & the Bristol Advanced Computing Research Centre (http://www.bris.ac.uk/acrc/) (D.J.L.); Wellcome Trust grant 098051 (Q.A.; C.T.-S. and Y.X.); Wellcome Trust Senior Research Fellowship grant 100719/Z/12/Z (M.G.T.); Young Explorers Grant from the National Geographic Society (8900-11) (C.A.E.); ERC Consolidator Grant 647787 ‘LocalAdaptatio’ (A.Ma.); Program of the RAS Presidium “Basic research for the development of the Russian Arctic” (B.M.); Russian Foundation for Basic Research grant 16-06-00303 (E.B.); a Rutherford Fellowship (RDF-10-MAU-001) from the Royal Society of New Zealand (M.P.C.)

Distinct roles of angiotensin receptors in autonomic dysreflexia following high-level spinal cord injury in mice

Autonomic dysreflexia (AD), a syndrome caused by loss of supraspinal control over sympathetic activity and amplified vascular reflex upon sensory stimuli below injury level, is a major health problem in high-level spinal cord injury (SCI). After supraspinal sympathetic control of the vasculature below the lesion is lost, the renin-angiotensin system (RAS) is thought to be involved in AD by regulating blood pressure and vascular reactivity. In this study, we aimed to assess the role of different RAS receptors during AD following SCI. Therefore, we induced AD by colorectal distention (CRD) in wild-type mice and mice deficient in the RAS components angiotensin (Ang) II type 1a receptor (AT1a) (Agtr1a(-/-)) and Ang-(1-7) receptor Mas (Mas(-/-)) four weeks after complete transection of spinal cord at thoracic level 4 (T4). Systemic blood pressure measurements and wire myography technique were performed to assess hemodynamics and the reactivity of peripheral arteries, respectively. CRD increased mean arterial blood pressure (MAP) and decreased heart rate (HR) in all three animal groups. However, we found less increases in MAP in Mas(-/-) mice compared to control mice after CRD, whereas AT1a deficiency did not affect the hemodynamic response. We found that the reactivity of wild-type and Mas(-/-) mesenteric arteries, which are innervated from ganglia distal but close to thoracic level T4, was diminished in response to Ang II in AD after T4-SCI, but this difference was not observed in the absence of AT1a receptors. CRD did not influence the reactivity of femoral arteries which are innervated from ganglia more distal to thoracic level T4, in response to Ang II in AD. In conclusion, we identified a specific role of the Ang-(1-7) receptor Mas in regulating the systemic blood pressure increase in AD in T4-SCI mice. Furthermore, AT1a signaling is not involved in this hemodynamic response, but underlies increased vascular reactivity in mesenteric arteries in response to Ang II, where it may contribute to adaptive changes in regional blood flow

Cardiomyocyte-derived CXCL12 is not involved in cardiogenesis but plays a crucial role in myocardial infarction

The chemokine CXCL12/SDF-1 is crucial for heart development and affects cardiac repair processes due to its ability to attract leukocytes and stem cells to injured myocardium. However, there is a great controversy whether CXCL12 is beneficial or detrimental after myocardial infarction (MI). The divergence in the reported CXCL12 actions may be due to the cellular source and time of release of the chemokine after MI. This study was designed to evaluate the role of cardiomyocyte-derived CXCL12 for cardiogenesis and heart repair after MI. We generated two rodent models each targeting CXCL12 in only one cardiac cell type: cardiomyocyte-specific CXCL12-overexpressing transgenic (Tg) rats and CXCL12 conditional knockout (cKO) mice. Animals of both models did not show any signs of cardiac abnormalities under baseline conditions. After induction of MI, cKO mice displayed preserved cardiac function and remodeling. Moreover, fibrosis was less pronounced in the hearts of cKO mice after MI. Accordingly, CXCL12 Tg rats revealed impaired cardiac function post-MI accompanied by enhanced fibrosis. Furthermore, we observed decreased numbers of infiltrating Th1 cells in the hearts of cKO mice. Collectively, our findings demonstrate that cardiomyocyte-derived CXCL12 is not involved in cardiac development but has adverse effects on the heart after injury via promotion of inflammation and fibrosis