Loss-of-function mutations in bone morphogenetic protein receptor II (BMP-RII) are linked to pulmonary arterial hypertension (PAH); the ligand for BMP-RII, BMP-2, is a negative regulator of SMC growth. Here, we report an interplay between PPARγ and its transcriptional target apoE downstream of BMP-2 signaling. BMP-2/BMP-RII signaling prevented PDGF-BB-induced proliferation of human and murine pulmonary artery SMCs (PASMCs) by decreasing nuclear phospho-ERK and inducing DNA binding of PPARγ that is independent of Smad1/5/8 phosphorylation. Both BMP-2 and a PPARγ agonist stimulated production and secretion of apoE by SMCs. Using a variety of methods, including short hairpin RNAi in human PASMCs, PAH patient-derived BMP-RII mutant PASMCs, a PPARγ antagonist, and PASMCs isolated from PPARγ-and apoE-deficient mice, we demonstrated that the antiproliferative effect of BMP-2 was BMP-RII, PPARγ, and apoE dependent. Furthermore, we created mice with targeted deletion of PPARγ in SMCs and showed that they spontaneously developed PAH, as indicated by elevated RV systolic pressure, RV hypertrophy, and increased muscularization of the distal pulmonary arteries. Thus, PPARγ-mediated events could protect against PAH, and PPARγ agonists may reverse PAH in patients with or without BMP-RII dysfunction.
Background-Patients with pulmonary arterial hypertension (PAH) have reduced expression of apolipoprotein E (apoE)and peroxisome proliferator-activated receptor-␥ in lung tissues, and deficiency of both has been linked to insulin resistance. ApoE deficiency leads to enhanced platelet-derived growth factor signaling, which is important in the pathobiology of PAH. We therefore hypothesized that insulin-resistant apoE-deficient (apoE Ϫ/Ϫ ) mice would develop PAH that could be reversed by a peroxisome proliferator-activated receptor-␥ agonist (eg, rosiglitazone). Methods and Results-We report that apoEϪ/Ϫ mice on a high-fat diet develop PAH as judged by elevated right ventricular systolic pressure. Compared with females, male apoE Ϫ/Ϫ were insulin resistant, had lower plasma adiponectin, and had higher right ventricular systolic pressure associated with right ventricular hypertrophy and increased peripheral pulmonary artery muscularization. Because male apoE Ϫ/Ϫ mice were insulin resistant and had more severe PAH than female apoE Ϫ/Ϫ mice, we treated them with rosiglitazone for 4 and 10 weeks. This treatment resulted in markedly higher plasma adiponectin, improved insulin sensitivity, and complete regression of PAH, right ventricular hypertrophy, and abnormal pulmonary artery muscularization in male apoE Ϫ/Ϫ mice. We further show that recombinant apoE and adiponectin suppress platelet-derived growth factor-BB-mediated proliferation of pulmonary artery smooth muscle cells harvested from apoE Ϫ/Ϫ or C57Bl/6 control mice. Conclusions-We have shown that insulin resistance, low plasma adiponectin levels, and deficiency of apoE may be risk factors for PAH and that peroxisome proliferator-activated receptor-␥ activation can reverse PAH in an animal model. Key Words: apolipoproteins Ⅲ glucose Ⅲ hypercholesterolemia Ⅲ hypertension, pulmonary Ⅲ insulin Ⅲ metabolism Ⅲ PPAR gamma A lthough insulin resistance is associated with systemic cardiovascular disease, 1-3 it has not been implicated as a predisposing factor in pulmonary arterial hypertension (PAH). Several findings, however, support such an association. Patients with idiopathic PAH have reduced pulmonary mRNA expression of peroxisome proliferator-activated receptor gamma (PPAR␥), 4 a ligand-activated nuclear receptor and transcription factor that regulates adipogenesis and glucose metabolism. [5][6][7] They also have reduced pulmonary mRNA expression of apolipoprotein E (apoE), 8 a protective factor known to reduce circulating oxidized low-density lipoprotein and atherogenesis in the vessel wall. 9 Deficiency of both PPAR␥ and apoE has been linked to insulin resistance and the metabolic syndrome. 7,9 Elevated levels of several circulating factors that are normally repressed by PPAR␥ are associated with insulin resistance 3 and implicated in the pathobiology of PAH. These include interleukin-6, 10,11 fractalkine, 12,13 monocyte chemoattractant protein-1, 14 endothelin-1 (ET-1), [15][16][17] and the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADM...
physiological characterization of RV remodeling in a murine model of pulmonary stenosis. Am J Physiol Heart Circ Physiol 295: H1351-H1368, 2008. First published June 27, 2008 doi:10.1152/ajpheart.91526.2007 dysfunction is a common long-term complication in patients after the repair of congenital heart disease. Previous investigators have examined the cellular and molecular mechanisms of left ventricular (LV) remodeling, but little is known about the stressed RV. Our purpose was to provide a detailed physiological characterization of a model of RV hypertrophy and failure, including RV-LV interaction, and to compare gene alterations between afterloaded RV versus LV. Pulmonary artery constriction was performed in 86 mice. Mice with mild and moderate pulmonary stenosis (PS) developed stable hypertrophy without decompensation. Mice with severe PS developed edema, decreased RV function, and high mortality. Tissue Doppler imaging demonstrated septal dyssynchrony and deleterious RV-LV interaction in the severe PS group. Microarray analysis showed 196 genes with increased expression and 1,114 with decreased expression. Several transcripts were differentially increased in the afterloaded RV but not in the afterloaded LV, including clusterin, neuroblastoma suppression of tumorigenicity 1, Dkk3, Sfrp2, formin binding protein, annexin A7, and lysyl oxidase. We have characterized a murine model of RV hypertrophy and failure, providing a platform for studying the physiological and molecular events of RV remodeling. Although the molecular responses of the RV and LV to afterload stress are mostly concordant, there are several key differences, which may represent targets for RV failure-specific therapy. gene expression; right ventricle; tetralogy of Fallot THE RIGHT VENTRICLE IS UNIQUELY at risk in patients with complex congenital heart disease involving right-sided obstructive lesions (e.g., tetralogy of Fallot, tetralogy/pulmonary atresia) and in patients with systemic right ventricles (1,40,46). Increased stress on the right ventricle in the form of increased hemodynamic loading (pressure and/or volume) may result in abnormalities in cardiac structure, function, metabolism, coronary perfusion, neurohormonal activation, and molecular signaling. These stresses lead to both adaptive and maladaptive structural and molecular remodeling of the right ventricle and deleterious effects on the left ventricle through ventricular-ventricular interaction and may limit long-term survival (3,7,29,42). For many of these patients, detrimental conditions for the right ventricle exist throughout life, even after successful repair or palliation. As surgical techniques for the primary repair of complex forms of congenital heart disease improve, long-term survival and quality of life will depend on our ability to preserve long-term right ventricular (RV) function. Decisions regarding the ideal time for surgical reintervention will need to be based on more quantitative rather than qualitative measures.Developing a better understanding of the molecu...
IMPORTANCECow's milk formula (CMF) is used to supplement breastfeeding (BF) at birth without clear clinical evidence to support the practice.OBJECTIVE To determine whether avoiding supplementation with CMF at birth can decrease risks of sensitization to cow's milk protein and/or clinical food allergy, including cow's milk allergy (CMA), overall and in subgroups stratified by 25-hydroxyvitamin D (25[OH]D) levels. DESIGN, SETTING, AND PARTICIPANTSThe Atopy Induced by Breastfeeding or Cow's Milk Formula (ABC) trial, a randomized, nonblinded clinical trial, began enrollment October 1, 2013, and completed follow-up May 31, 2018, at a single university hospital in Japan. Participants included 330 newborns at risk for atopy; of these, 312 were included in the analysis. Data were analyzed from September 1 through October 31, 2018.INTERVENTIONS Immediately after birth, newborns were randomized (1:1 ratio) to BF with or without amino acid-based elemental formula (EF) for at least the first 3 days of life (BF/EF group) or BF supplemented with CMF (Ն5 mL/d) from the first day of life to 5 months of age (BF plus CMF group). MAIN OUTCOMES AND MEASURESThe primary outcome was sensitization to cow's milk (IgE level, Ն0.35 allergen units [U A ]/mL) at the infant's second birthday. Secondary outcomes were immediate and anaphylactic types of food allergy, including CMA, diagnosed by oral food challenge test or triggered by food ingestion, with food-specific IgE levels of at least 0.35 U A /mL. Subgroup analysis was prespecified by tertiles of serum 25(OH)D levels at 5 months of age. RESULTSOf the 312 infants included in the analysis (160 female [51.3%] and 152 male [48.7%]), 151 of 156 (96.8%) in the BF/EF and BF plus CMF groups were followed up until their second birthday. The primary outcome occurred in 24 infants (16.8%) in the BF/EF group, which was significantly fewer than the 46 infants (32.2%) in the BF plus CMF group (relative risk [RR], 0.52; 95% CI, 0.34-0.81). The middle tertile of the 25(OH)D subgroup, but not the low and high tertiles, had a significant interaction with the intervention (RR, 0.19; 95% CI, 0.07-0.50; P = .02). The prevalence of food allergy at the second birthday was significantly lower in the BF/EF than in the BF plus CMF groups for immediate (4 [2.6%] vs 20 [13.2%]; RR, 0.20; 95% CI, 0.07-0.57) and anaphylactic (1 [0.7%] vs 13 [8.6%]; RR, 0.08; 95% CI, 0.01-0.58) types. CONCLUSIONS AND RELEVANCEThe evidence suggests that sensitization to cow's milk and food allergy, including CMA and anaphylaxis, are primarily preventable by avoiding CMF supplementation for at least the first 3 days of life.TRIAL REGISTRATION http://umin.ac.jp Identifier: UMIN000011577
Recent data suggest that beta-adrenergic receptor subtypes couple differentially to signaling pathways regulating cardiac function vs. cardiac remodeling. To dissect the roles of beta1- vs. beta2-receptors in the pathogenesis of cardiomyopathy, doxorubicin was administered to beta1, beta2, and beta1/beta2 knockout (-/-) and wild-type mice. Expression and activation of MAPKs were measured. Wild-type and beta1-/- mice showed no acute cardiovascular effects, whereas beta2-/- mice all died within 30 min. The additional deletion of the beta1-receptor (beta1/beta2-/-) totally rescued this toxicity. beta2-/- mice developed decreased contractile function, hypotension, QTc prolongation, and ST segment changes and a 20-fold increase in p38 MAPK activity not seen in the other genotypes. The MAPK inhibitor SB-203580 rescued beta2-/- mice from this acute toxicity. The enhanced toxicity in beta2-/- mice was also recapitulated in wild-type mice with the beta2-selective antagonist ICI-118,551, although the rescue effect of the beta1-deletion was not recapitulated using the beta1-selective antagonist metoprolol or the nonselective beta-antagonist propranolol. These data suggest that beta2-adrenergic receptors play a cardioprotective role in the pathogenesis of cardiomyopathy, whereas beta1-adrenergic receptors mediate at least some of the acute cardiotoxicity of anthracyclines. Differential activation of MAPK isoforms, previously shown in vitro to regulate beta-agonist as well as doxorubicin cardiotoxicity, appears to play a role in mediating the differential effects of these beta-adrenergic receptor subtypes in vivo.
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