RESUMEN
The dysfunctional nature of CD34 cells from patients with heart failure (HF) may make them unsuitable for autologous stem-cell therapy. In view of evidence that the vasoprotective axis of the renin-angiotensin system (RAS) improves CD34 cell functions, we hypothesized that CD34 cells from patients with HF will be dysfunctional and that angiotensin-(1-7) [Ang-(1-7)] would improve their function. Peripheral blood was collected from New York Heart Association class II-IV patients with HF (n = 31) and reference subjects (n = 16). CD34 cell numbers from patients with HF were reduced by 47% (P < 0.05) and also displayed 76% reduction in migratory capacity and 56% (P < 0.05) lower production of nitric oxide. These alterations were associated with increases in RAS genes angiotensin-converting enzyme and AT2R (595%, P < 0.05) mRNA levels and 80% and 85% decreases in angiotensin-converting enzyme 2 and Mas mRNA levels, respectively. Treatment with Ang-(1-7) enhanced CD34 cell function through increased migratory potential and nitric oxide production, and reduced reactive oxygen species generation. These data show that HF CD34 cells are dysfunctional, and Ang-(1-7) improves their functions. This suggests that activation of the vasoprotective axis of the RAS may hold therapeutic potential for autologous stem-cell therapy in patients with HF.
Asunto(s)
Angiotensina I/farmacología , Antígenos CD34/metabolismo , Insuficiencia Cardíaca/metabolismo , Células Madre Hematopoyéticas/efectos de los fármacos , Fragmentos de Péptidos/farmacología , Estudios de Casos y Controles , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Femenino , Insuficiencia Cardíaca/patología , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/patología , Humanos , Masculino , Persona de Mediana Edad , Óxido Nítrico/metabolismo , Fenotipo , Especies Reactivas de Oxígeno/metabolismo , Sistema Renina-Angiotensina/efectos de los fármacos , Sistema Renina-Angiotensina/genéticaRESUMEN
RATIONALE: Sympathetic nervous system control of inflammation plays a central role in hypertension. The gut receives significant sympathetic innervation, is densely populated with a diverse microbial ecosystem, and contains immune cells that greatly impact overall inflammatory homeostasis. Despite this uniqueness, little is known about the involvement of the gut in hypertension. OBJECTIVE: Test the hypothesis that increased sympathetic drive to the gut is associated with increased gut wall permeability, increased inflammatory status, and microbial dysbiosis and that these gut pathological changes are linked to hypertension. METHODS AND RESULTS: Gut epithelial integrity and wall pathology were examined in spontaneously hypertensive rat and chronic angiotensin II infusion rat models. The increase in blood pressure in spontaneously hypertensive rat was associated with gut pathology that included increased intestinal permeability and decreased tight junction proteins. These changes in gut pathology in hypertension were associated with alterations in microbial communities relevant in blood pressure control. We also observed enhanced gut-neuronal communication in hypertension originating from paraventricular nucleus of the hypothalamus and presenting as increased sympathetic drive to the gut. Finally, angiotensin-converting enzyme inhibition (captopril) normalized blood pressure and was associated with reversal of gut pathology. CONCLUSIONS: A dysfunctional sympathetic-gut communication is associated with gut pathology, dysbiosis, and inflammation and plays a key role in hypertension. Thus, targeting of gut microbiota by innovative probiotics, antibiotics, and fecal transplant, in combination with the current pharmacotherapy, may be a novel strategy for hypertension treatment.
Asunto(s)
Microbioma Gastrointestinal/fisiología , Hipertensión/metabolismo , Hipertensión/fisiopatología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/fisiopatología , Angiotensina II/toxicidad , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Mucosa Intestinal/efectos de los fármacos , Masculino , Permeabilidad/efectos de los fármacos , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Ratas Sprague-Dawley , Ratas WistarRESUMEN
The health of the cardiovascular and pulmonary systems is inextricably linked to the renin-angiotensin system (RAS). Physiologically speaking, a balance between the vasodeleterious (Angiotensin-converting enzyme [ACE]/Angiotensin II [Ang II]/Ang II type 1 receptor [AT1R]) and vasoprotective (Angiotensin-converting enzyme 2 [ACE2]/Angiotensin-(1-7) [Ang-(1-7)]/Mas receptor [MasR]) components of the RAS is critical for cardiopulmonary homeostasis. Upregulation of the ACE/Ang II/AT1R axis shifts the system toward vasoconstriction, proliferation, hypertrophy, inflammation, and fibrosis, all factors that contribute to the development and progression of cardiopulmonary diseases. Conversely, stimulation of the vasoprotective ACE2/Ang-(1-7)/MasR axis produces a counter-regulatory response that promotes cardiovascular health. Current research is investigating novel strategies to augment actions of the vasoprotective RAS components, particularly ACE2, in order to treat various pathologies. Although multiple approaches to increase the activity of ACE2 have displayed beneficial effects against experimental disease models, the mechanisms behind its protective actions remain incompletely understood. Recent work demonstrating a non-catalytic role for ACE2 in amino acid transport in the gut has led us to speculate that the therapeutic effects of ACE2 can be mediated, in part, by its actions on the gastrointestinal tract and/or gut microbiome. This is consistent with emerging data which suggest that dysbiosis of the gut and lung microbiomes is associated with cardiopulmonary disease. This review highlights new developments in the protective actions of ACE2 against cardiopulmonary disorders, discusses innovative approaches to targeting ACE2 for therapy, and explores an evolving role for gut and lung microbiota in cardiopulmonary health.
Asunto(s)
Sistemas de Liberación de Medicamentos/tendencias , Cardiopatías/tratamiento farmacológico , Enfermedades Pulmonares/tratamiento farmacológico , Microbiota/efectos de los fármacos , Peptidil-Dipeptidasa A/metabolismo , Enzima Convertidora de Angiotensina 2 , Animales , Fármacos Cardiovasculares/administración & dosificación , Cardiopatías/enzimología , Cardiopatías/microbiología , Humanos , Enfermedades Pulmonares/enzimología , Enfermedades Pulmonares/microbiología , Microbiota/fisiología , Peptidil-Dipeptidasa A/genética , Polimorfismo Genético/genética , Proto-Oncogenes MasRESUMEN
Angiotensin-converting enzyme 2 (ACE2) plays a critical role against myocardial infarction (MI). We hypothesized that activation of intrinsic ACE2 would be protective against ischemia-induced cardiac pathophysiology. Diminazene aceturate (DIZE), a small molecule ACE2 activator, has been used to evaluate this hypothesis. DIZE (15 mg/kg per day, s.c.) was injected 2 days before MI surgery and continued throughout the study period. MI rats showed a 62% decrease in fractional shortening (%; control, 51.1±3.2; DIZE alone, 52.1±3.2; MI, 19.1±3.0), a 55% decrease in contractility (dP/dtmax mm Hg/s; control, 9480±425.3; DIZE alone, 9585±597.4; MI, 4251±657.7), and a 27% increase in ventricular hypertrophy (mg/mm; control, 26.5±1.5; DIZE alone, 26.9±1.4; MI, 33.4±1.1). DIZE attenuated the MI-induced decrease in fractional shortening by 89%, improved dP/dtmax by 92%, and reversed ventricular hypertrophy by 18%. MI also significantly increased ACE and angiotensin type 1 receptor levels but decreased ACE2 activity by 40% (control, 246.2±25.1; DIZE alone, 254.2±20.6; MI, 148.9±29.2; RFU/min), which was reversed by DIZE treatment. Thus, DIZE treatment decreased the infarct area, attenuated LV remodeling post-MI, and restored normal balance of the cardiac renin-angiotensin system. In addition, DIZE treatment increased circulating endothelial progenitor cells, increased engraftment of cardiac progenitor cells, and decreased inflammatory cells in peri-infarct cardiac regions. All of the beneficial effects associated with DIZE treatment were abolished by C-16, an ACE2 inhibitor. Collectively, DIZE and DIZE-like small molecules may represent promising new therapeutic agents for MI.
Asunto(s)
Diminazeno/análogos & derivados , Corazón/efectos de los fármacos , Infarto del Miocardio/prevención & control , Isquemia Miocárdica/prevención & control , Peptidil-Dipeptidasa A/metabolismo , Enzima Convertidora de Angiotensina 2 , Animales , Apoptosis/efectos de los fármacos , Diminazeno/farmacología , Diminazeno/uso terapéutico , Corazón/fisiopatología , Hemodinámica/efectos de los fármacos , Macrófagos/efectos de los fármacos , Infarto del Miocardio/enzimología , Infarto del Miocardio/fisiopatología , Isquemia Miocárdica/enzimología , Isquemia Miocárdica/fisiopatología , Miocardio/enzimología , Ratas , Ratas Sprague-Dawley , Receptor de Angiotensina Tipo 1/metabolismo , Sistema Renina-Angiotensina/efectos de los fármacos , Sistema Renina-Angiotensina/fisiología , Células Madre/efectos de los fármacosRESUMEN
In the prenatal heart, right-to-left atrial shunting of blood through the foramen ovale is essential for proper circulation. After birth, as the pulmonary circulation is established, the foramen ovale functionally closes as a result of changes in the relative pressure of the two atrial chambers, ensuring the separation of oxygen depleted venous blood in the right atrium from the oxygenated blood entering the left atrium. Little is known regarding the process of anatomical closure of the foramen ovale in the postnatal heart. Genetically engineered mouse models are powerful tools to study heart development and to reveal mechanisms underlying cardiac anomalies, including defects in atrioventricular septation. Using three-dimensional reconstructions of serial sectioned hearts at early postnatal Days 2-7, we show a progressive reduction in the size of the interatrial communication throughout this period and complete closure by postnatal Day 7. Furthermore we demonstrate that fusion of the septum primum and septum secundum occurs between 4 weeks and 3 months of age. This study provides a standard timeline for morphological closure of the right-left atrial communication and fusion between the atrial septa in normal mouse hearts.
Asunto(s)
Foramen Oval/anatomía & histología , Corazón/anatomía & histología , Factores de Edad , Envejecimiento , Animales , Animales Recién Nacidos , Circulación Coronaria , Modelos Animales de Enfermedad , Foramen Oval/anomalías , Foramen Oval/fisiología , Foramen Oval Permeable/genética , Foramen Oval Permeable/patología , Corazón/fisiología , Defectos del Tabique Interatrial/genética , Defectos del Tabique Interatrial/patología , Hemodinámica , Procesamiento de Imagen Asistido por Computador , Imagenología Tridimensional , Ratones , Ratones Transgénicos , Morfogénesis , Circulación Pulmonar , Coloración y EtiquetadoRESUMEN
Atrial natriuretic factor (ANF) is abundantly expressed in atrial cardiomyocytes throughout ontogeny and in ventricular cardiomyocytes in the developing heart. However, during cardiac failure and hypertrophy, ANF expression can reappear in adult ventricular cardiomyocytes. The transcription factor Nkx2-5 is one of the major transactivators of the ANF gene in the developing heart. We identified Nkx2-5 binding at three 5' regulatory elements (kb -34, -31, and -21) and at the proximal ANF promoter by ChIP assay using neonatal mouse cardiomyocytes. 3C analysis revealed close proximity between the distal elements and the promoter region. A 5.8-kb fragment consisting of these elements transactivated a reporter gene in vivo recapitulating endogenous ANF expression, which was markedly reduced in tamoxifen-inducible Nkx2-5 gene knockout mice. However, expression of a reporter gene was increased and expanded toward the outer compact layer in the absence of the transcription repressor Hey2, similar to endogenous ANF expression. Functional Nkx2-5 and Hey2 binding sites separated by 59 bp were identified in the -34 kb element in neonatal cardiomyocytes. In adult hearts, this fragment did not respond to pressure overload, and ANF was induced in the absence of Nkx2-5. These results demonstrate that Nkx2-5 and its responsive cis-regulatory DNA elements are essential for ANF expression selectively in the developing heart.