mIGF-1 regulates heart physiology and induces complete regeneration of infarcted myocardial tissue

ABSTRACT The mammalian heart is particularly susceptible to traumatic injury or sustained disease, suffering tissue deterioration, scarring and loss of contractile function. Clinical interventions to prevent or reverse the devastating effects of cardiac damage have met with limited success, presumably due to restricted cardiac regenerative potential. We tested the ability of a locally acting mIGF-1 isoform to regenerate the injured heart, restricting expression of a mIGF-1 transgene to the mouse myocardium to exclude endocrine effects on other tissues. Transgenic mIGF-1 hearts displayed accelerated postnatal cardiac growth that never exceeded the wild-type adult cardiac size. Early remodelling of the transgenic hearts was accompanied by transient activation of MAPKs and increased function of the translational machinery, without perturbing cardiac performance, and by modest upregulation of hypertrophic markers at one and two months. Notably, AKT the downstream effector of IGF-1 signalling was not activated in the hearts of transgenic mIGF-1 animals, indicating that a different kinase regulates mIGF-1 downstream signalling in the heart. The regenerative capacity of mIGF-1 was analyzed either by LAD ligation or by direct cardiotoxin (CTX) injection into the ventricles of adult mice. Injury to both wild-type and transgenic mIGF-1 hearts produced reproducible and localized infarctions coupled with early cell death and marked inflammation. In contrast to the characteristic progression of scar formation in wild-type hearts, transgenic mIGF-1 hearts induced complete repair of the injured tissue after 1 month, without scar formation. mIGF-1-induced regeneration was associated with a marked decrease in pro-inflammatory cytokines and an increase in anti-inflammatory cytokines, indicating that mIGF-1 drives regeneration in part by modulating the inflammatory response in pathological conditions. At later stages, mIGF-1 transgenic hearts displayed increased proliferative activity proximal to the infarct, and restored cardiac functionality. By enabling myocardial reconstruction following injury, the mIGF-1 isoform appears to bypass the evolutionary restrictions on mammalian regeneration. The enhancement of cardiac regeneration by localized expression of this growth factor suggests novel and clinically feasible therapeutic strategies to decrease inflammation and increase cell replacement after tissue damage

growth factor enhancement of cardiac regeneration

The potential for endogenous or supplementary stem cells to restore the form and function of damaged tissues is particularly promising for overcoming the restricted regenerative capacity of the mammalian heart. To maintain blood circulation, this essential organ needs to launch a rapid response to repair damage of the muscle wall and to prevent muscle loss. The capacity of growth factors to supplement the repair process has been successfully applied to restore the integrity of damaged skeletal muscle, reducing the fibrotic response to injury, and recruiting local populations of self-renewing precursor cells and circulating stem cells. We review the recent evidence that extension of growth factor supplementation to the heart may overcome its inherent regenerative impediments through improvement of the local tissue environment and stimulation of cell replacement, and we speculate on future research directions for treatment of myocardial damage

Increased cardiogenesis in P19-GFP teratocarcinoma cells expressing the propeptide IGF-1Ea

AbstractThe mechanism implicated in differentiation of endogenous cardiac stem cells into cardiomyocytes to regenerate the heart tissue upon an insult remains elusive, limiting the therapeutical goals to exogenous cell injection and/or gene therapy. We have shown previously that cardiac specific overexpression of the insulin-like growth factor 1 propeptide IGF-1Ea induces beneficial myocardial repair after infarct. Although the mechanism is still under investigation, the possibility that this propeptide may be involved in promoting stem cell differentiation into the cardiac lineage has yet to be explored. To investigate whether IGF-1Ea promote cardiogenesis, we initially modified P19 embryonal carcinoma cells to express IGF-1Ea. Taking advantage of their cardiomyogenic nature, we analyzed whether overexpression of this propeptide affected cardiac differentiation program. The data herein presented showed for the first time that constitutively overexpressed IGF-1Ea increased cardiogenic differentiation program in both undifferentiated and DMSO-differentiated cells. In details, IGF-1Ea overexpression promoted localization of alpha-actinin in finely organized sarcomeric structure compared to control cells and upregulated the cardiac mesodermal marker NKX-2.5 and the ventricular structural protein MLC2v. Furthermore, activated IGF-1 signaling promoted cardiac mesodermal induction in undifferentiated cells independently of cell proliferation. This analysis suggests that IGF-1Ea may be a good candidate to improve both in vitro production of cardiomyocytes from pluripotent stem cells and in vivo activation of the differentiation program of cardiac progenitor cells

Local IGF-1 isoform protects cardiomyocytes from hypertrophic and oxidative stresses via SirT1 activity

Oxidative and hypertrophic stresses contribute to the pathogenesis of heart failure. Insulin-like growth factor-1 (IGF-1) is a peptide hormone with a complex post-transcriptional regulation, generating distinct isoforms. Locally acting IGF-1 isoform (mIGF-1) helps the heart to recover from toxic injury and from infarct. In the murine heart, moderate overexpression of the NAD+-dependent deacetylase SirT1 was reported to mitigate oxidative stress. SirT1 is known to promote lifespan extension and to protect from metabolic challenges. Circulating IGF-1 and SirT1 play antagonizing biological roles and share molecular targets in the heart, in turn affecting cardiomyocyte physiology. However, how different IGF-1 isoforms may impact SirT1 and affect cardiomyocyte function is unknown. Here we show that locally acting mIGF-1 increases SirT1 expression/activity, whereas circulating IGF-1 isoform does not affect it, in cultured HL-1 and neonatal cardiomyocytes. mIGF-1-induced SirT1 activity exerts protection against angiotensin II (Ang II)-triggered hypertrophy and against paraquat (PQ) and Ang II-induced oxidative stress. Conversely, circulating IGF-1 triggered itself oxidative stress and cardiomyocyte hypertrophy. Interestingly, potent cardio-protective genes (adiponectin, UCP-1 and MT-2) were increased specifically in mIGF-1-overexpressing cardiomyocytes, in a SirT1-dependent fashion. Thus, mIGF-1 protects cardiomyocytes from oxidative and hypertrophic stresses via SirT1 activity, and may represent a promising cardiac therapeutic

Canales cortos de comercialización. Las TIC en pandemia y postpandemia

En las últimas décadas se han evidenciado formas más directas de vinculación entre los ámbitos de la producción y de consumo de alimentos que responden a cambios en las prácticas sociales en lo referente a los modos de comercialización. Estas nuevas formas de vinculación entre la producción y el consumo de alimentos son denominados como canales cortos de comercialización, circuitos de proximidad, redes alimentarias alternativas, entre otros términos. En general, los autores identifican las siguientes características: (i) resignifican del valor del alimento, no solo como fuente de nutriente sino como constructor de ciudadanía, territorio, en el cual se resignifican el lugar de procedencia y las características de elaboración (Renting et al., 2003; Marsden et al. 2000: Sonnino y Marsden, 2006) (ii) relaciones estrechas entre el ámbito de la producción, la comercialización y el consumo, donde no solo fluye lo material (el bien o servicio que media una transacción económica), sino también lo inmaterial, como los conocimientos, la información, valores visiones y formas de vida compartida (Cendón et al., 2021), (iii) Las relaciones de compra-venta, se complementan con talleres, cursos, jornadas , información, educación y otros eventos en relación con la comunidad (Viteri et al., 2020).EEA BalcarceFil: Santini, Santiago. Instituto Nacional de Tecnología Agropecuaria (INTA) Estación Experimental Agropecuaria Balcarce; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto de Innovación para la Producción Agropecuaria y el Desarrollo Sostenible; Argentina.Fil: Cendón, María Laura. Instituto Nacional de Tecnología Agropecuaria (INTA) Estación Experimental Agropecuaria Balcarce; Argentina.Fil: Cendón, María Laura. Universidad Nacional de Mar del Plata. Facultad de Humanidades; ArgentinaFil: Bruno, Mariana Paola. Instituto Nacional de Tecnología Agropecuaria (INTA) Estación Experimental Agropecuaria Balcarce; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto de Innovación para la Producción Agropecuaria y el Desarrollo Sostenible; Argentina

Lutzomyia longipalpis presence and abundance distribution at different microspatial scales in an urban scenario

The principal objective of this study was to assess a modeling approach to Lu. longipalpis distribution in an urban scenario, discriminating micro-scale landscape variables at microhabitat and macrohabitat scales and the presence from the abundance of the vector. For this objective, we studied vectors and domestic reservoirs and evaluated different environmental variables simultaneously, so we constructed a set of 13 models to account for microhabitats, macro-habitats and mixed-habitats. We captured a total of 853 sandflies, of which 98.35% were Lu. longipalpis.We sampled a total of 197 dogs; 177 of which were associated with households where insects were sampled. Positive rK39 dogs represented 16.75% of the total, of which 47% were asymptomatic. Distance to the border of the city and high to medium density vegetation cover ended to be the explanatory variables, all positive, for the presence of sandflies in the city. All variables in the abundance model ended to be explanatory, trees around the trap, distance to the stream and its quadratic, being the last one the only one with negative coefficient indicating that the maximum abundance was associated with medium values of distance to the stream. The spatial distribution of dogs infected with L. infantum showed a heterogeneous pattern throughout the city; however, we could not confirm an association of the distribution with the variables assessed. In relation to Lu. longipalpis distribution, the strategy to discriminate the micro-spatial scales at which the environmental variables were recorded allowed us to associate presence with macrohabitat variables and abundance with microhabitat and macrohabitat variables. Based on the variables associated with Lu. longipalpis, the model will be validated in other cities and environmental surveillance, and control interventions will be proposed and evaluated in the microscale level and integrated with socio-cultural approaches and programmatic and village (mesoscale) strategies.Fil: Santini, Maria Soledad. Dirección Nacional de Institutos de Investigación. Administración Nacional de Laboratorios e Institutos de Salud. Centro Nacional de Diagnóstico e Investigaciones Endemo-epidémicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Red de Investigación de la Leishmaniasis en Argentina; ArgentinaFil: Utgés, María Eugenia. Red de Investigación de la Leishmaniasis en Argentina; Argentina. Ministerio de Salud. Instituto Nacional de Medicina Tropical; ArgentinaFil: Berrozpe, Pablo Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Red de Investigación de la Leishmaniasis en Argentina; Argentina. Ministerio de Salud. Instituto Nacional de Medicina Tropical; ArgentinaFil: Manteca Acosta, Mariana. Ministerio de Salud. Instituto Nacional de Medicina Tropical; Argentina. Red de Investigación de la Leishmaniasis en Argentina; ArgentinaFil: Casas, Natalia. Red de Investigación de la Leishmaniasis en Argentina; Argentina. Ministerio de Salud. Programa Nacional de Control de Enfermedades Zoonóticas.; ArgentinaFil: Heuer, Paola. Fundación Héctor A. Barceló. Laboratorio de Control de Vectores Entomológicos de Importancia Sanitaria; ArgentinaFil: Salomón, Oscar Daniel. Ministerio de Salud. Instituto Nacional de Medicina Tropical; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Red de Investigación de la Leishmaniasis en Argentina; Argentin

A naturally occurring calcineurin variant inhibits FoxO activity and enhances skeletal muscle regeneration

The calcium-activated phosphatase calcineurin (Cn) transduces physiological signals through intracellular pathways to influence the expression of specific genes. Here, we characterize a naturally occurring splicing variant of the CnAβ catalytic subunit (CnAβ1) in which the autoinhibitory domain that controls enzyme activation is replaced with a unique C-terminal region. The CnAβ1 enzyme is constitutively active and dephosphorylates its NFAT target in a cyclosporine-resistant manner. CnAβ1 is highly expressed in proliferating myoblasts and regenerating skeletal muscle fibers. In myoblasts, CnAβ1 knockdown activates FoxO-regulated genes, reduces proliferation, and induces myoblast differentiation. Conversely, CnAβ1 overexpression inhibits FoxO and prevents myotube atrophy. Supplemental CnAβ1 transgene expression in skeletal muscle leads to enhanced regeneration, reduced scar formation, and accelerated resolution of inflammation. This unique mode of action distinguishes the CnAβ1 isoform as a candidate for interventional strategies in muscle wasting treatment

Ablation of SGK1 Impairs Endothelial Cell Migration and Tube Formation Leading to Decreased Neo-Angiogenesis Following Myocardial Infarction

Serum and glucocorticoid inducible kinase 1 (SGK1) plays a pivotal role in early angiogenesis during embryonic development. In this study, we sought to define the SGK1 downstream signalling pathways in the adult heart and to elucidate their role in cardiac neo-angiogenesis and wound healing after myocardial ischemia. To this end, we employed a viable SGK1 knockout mouse model generated in a 129/SvJ background. Ablation of SGK1 in these mice caused a significant decrease in phosphorylation of SGK1 target protein NDRG1, which correlated with alterations in NF-κB signalling and expression of its downstream target protein, VEGF-A. Disruption of these signalling pathways was accompanied by smaller heart and body size. Moreover, the lack of SGK1 led to defective endothelial cell (ECs) migration and tube formation in vitro, and increased scarring with decreased angiogenesis in vivo after myocardial infarct. This study underscores the importance of SGK1 signalling in cardiac neo-angiogenesis and wound healing after an ischemic insult in vivo