MicroRNA-138 and microRNA-25 down-regulate mitochondrial calcium uniporter, causing the pulmonary arterial hypertension cancer phenotype

Rationale: Pulmonary arterial hypertension (PAH) is an obstructive vasculopathy characterized by excessive pulmonary artery smooth muscle cell (PASMC) proliferation, migration, and apoptosis resistance. This cancer-like phenotype is promoted by increased cytosolic calcium ([Ca2+]cyto), aerobic glycolysis, and mitochondrial fission. Objectives: To determine how changes in mitochondrial calcium uniporter (MCU) complex (MCUC) function influence mitochondrial dynamics and contribute to PAH’s cancer-like phenotype. Methods: PASMCs were isolated from patients with PAH and healthy control subjects and assessed for expression of MCUC subunits. Manipulation of the pore-forming subunit, MCU, in PASMCs was achieved through small interfering RNA knockdown or MCU plasmid-mediated up-regulation, as well as through modulation of the upstream microRNAs (miRs) miR-138 and miR-25. In vivo, nebulized anti-miRs were administered to rats with monocrotaline-induced PAH. Measurements and Main Results: Impaired MCUC function, resulting from down-regulation of MCU and up-regulation of an inhibitory subunit, mitochondrial calcium uptake protein 1, is central to PAH’s pathogenesis. MCUC dysfunction decreases intramitochondrial calcium ([Ca2+]mito), inhibiting pyruvate dehydrogenase activity and glucose oxidation, while increasing [Ca2+]cyto, promoting proliferation, migration, and fission. In PAH PASMCs, increasing MCU decreases cell migration, proliferation, and apoptosis resistance by lowering [Ca2+]cyto, raising [Ca2+]mito, and inhibiting fission. In normal PASMCs, MCUC inhibition recapitulates the PAH phenotype. In PAH, elevated miRs (notably miR-138) down-regulate MCU directly and also by decreasing MCU’s transcriptional regulator cAMP response element–binding protein 1. Nebulized anti-miRs against miR-25 and miR-138 restore MCU expression, reduce cell proliferation, and regress established PAH in the monocrotaline model. Conclusions: These results highlight miR-mediated MCUC dysfunction as a unifying mechanism in PAH that can be therapeutically targeted

17β-Estradiol and estrogen receptor α protect right ventricular function in pulmonary hypertension via BMPR2 and apelin

Women with pulmonary arterial hypertension (PAH) exhibit better right ventricular (RV) function and survival than men; however, the underlying mechanisms are unknown. We hypothesized that 17β-estradiol (E2), through estrogen receptor α (ER-α), attenuates PAH-induced RV failure (RVF) by upregulating the procontractile and prosurvival peptide apelin via a BMPR2-dependent mechanism. We found that ER-α and apelin expression were decreased in RV homogenates from patients with RVF and from rats with maladaptive (but not adaptive) RV remodeling. RV cardiomyocyte apelin abundance increased in vivo or in vitro after treatment with E2 or ER-α agonist. Studies employing ER-α–null or ER-β–null mice, ER-α loss-of-function mutant rats, or siRNA demonstrated that ER-α is necessary for E2 to upregulate RV apelin. E2 and ER-α increased BMPR2 in pulmonary hypertension RVs and in isolated RV cardiomyocytes, associated with ER-α binding to the Bmpr2 promoter. BMPR2 is required for E2-mediated increases in apelin abundance, and both BMPR2 and apelin are necessary for E2 to exert RV-protective effects. E2 or ER-α agonist rescued monocrotaline pulmonary hypertension and restored RV apelin and BMPR2. We identified what we believe to be a novel cardioprotective E2/ER-α/BMPR2/apelin axis in the RV. Harnessing this axis may lead to novel RV-targeted therapies for PAH patients of either sex

New GPCRs from a human lingual cDNA library

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Correlations among quality parameters of peach fruit

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Optimal Parenthesizing of Geometric Algebra Products

International audienceManipulating objects using geometric algebra may involve several associative products in a single expression. For example, an object can be constructed by the outer product of multiple points. This number of products can be small for some conformal algebra and high for higher dimensional algebras such as quadric conformal geometric algebras. In these situations, the order of products (i.e. the choice of the parenthesis in the expression) should not change the final result but may change the overall computational cost, according to the grade of the intermediate multivectors. Indeed, the usual left to right way to evaluate the expression may not be most computationally efficient. Studies on the number of arithmetic operations of geometric algebra expressions have been limited to products of only two homogeneous multivectors. This paper shows that there exists an optimal order in the evaluation of an expression involving geometric and outer products, and presents a dynamic programming framework to find it

Constrained Dynamics in Conformal and Projective Geometric Algebra

In this paper we tackle the problem of constrained rigid body dynamics in the Conformal and Projective Geometric Algebras (CGA, PGA). First we construct a screw-theory based formulation of dynamics in CGA and note the equivalence between this and the PGA dynamics presented by Gunn in[1]. After verifying the formulation via simulation, we move on to the challenge of adding constraints. First we apply the standard mechanical engineering technique of virtual power to the constraint problem in our Geometric Algebra (GA) framework. We then discuss a novel technique for ‘pinning’ dynamic rigid bodies to geometric primitives, a technique that relies on the invariance of certain multivectors and functions of multivectors to specific rotor transformations

Croissance, chute et qualite des fruits chez le pecher. Mesure de la variabilite intra arbres et recherche des facteurs explicatifs. Rapport final 1990

Convention INRA-Region PACA : Etude no.90.03399-90.03400. Document interne *INRA, Station d'agronomie Montfavet (FRA) Diffusion du document : INRA, Station d'agronomie Montfavet (FRA)National audienc