RESUMEN
Heart failure with preserved ejection fraction (HFpEF) is highly prevalent, and lacks effective treatment. The aberration of WNT pathway underlies many pathological processes including cardiac fibrosis and hypertrophy, while porcupine is an acyltransferase essential for the secretion of WNT ligands. In this study we investigated the role of WNT signaling pathway in HFpEF as well as whether blocking WNT signaling by a novel porcupine inhibitor CGX1321 alleviated HFpEF. We established two experimental HFpEF mouse models, namely the UNX/DOCA model and high fat diet/L-NAME ("two-hit") model. The UNX/DOCA and "two-hit" mice were treated with CGX1321 (3 mg·kg-1·d-1) for 4 and 10 weeks, respectively. We showed that CGX1321 treatment significantly alleviated cardiac hypertrophy and fibrosis, thereby improving cardiac diastolic function and exercise performance in both models. Furthermore, both canonical and non-canonical WNT signaling pathways were activated, and most WNT proteins, especially WNT3a and WNT5a, were upregulated during the development of HEpEF in mice. CGX1321 treatment inhibited the secretion of WNT ligands and repressed both canonical and non-canonical WNT pathways, evidenced by the reduced phosphorylation of c-Jun and the nuclear translocation of ß-catenin and NFATc3. In an in vitro HFpEF model, MCM and ISO-treated cardiomyocytes, knockdown of porcupine by siRNA leads to a similar inhibitory effect on WNT pathways, cardiomyocyte hypertrophy and cardiac fibroblast activation as CGX1321 did, whereas supplementation of WNT3a and WNT5a reversed the anti-hypertrophy and anti-fibrosis effect of CGX1321. We conclude that WNT signaling activation plays an essential role in the pathogenesis of HFpEF, and porcupine inhibitor CGX1321 exerts a therapeutic effect on HFpEF in mice by attenuating cardiac hypertrophy, alleviating cardiac fibrosis and improving cardiac diastolic function.
Asunto(s)
Cardiomiopatías , Acetato de Desoxicorticosterona , Insuficiencia Cardíaca , Animales , Ratones , Cardiomegalia/patología , Cardiomiopatías/patología , Acetato de Desoxicorticosterona/farmacología , Acetato de Desoxicorticosterona/uso terapéutico , Fibrosis , Insuficiencia Cardíaca/metabolismo , Miocitos Cardíacos , Volumen Sistólico/fisiología , Vía de Señalización WntRESUMEN
Background: Whether combination administration of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and beta-blockers (BBs) has a "reversal" effect on cardiac structure and function for first-diagnosed idiopathic dilated cardiomyopathy (FSIDCM) patients with unclear etiologies and inducements is unknown. Materials and Methods: We studied the effect of the protocol on FSIDCM patients. The effect was investigated in 26 FSIDCM patients. The criteria of "complete reversal" included left ventricular end-diastolic diameter (LVEDD) ≤50 mm for females or ≤55 mm for males and left ventricular ejection fraction (LVEF) ≥45%; the criteria of "partial reversal" was the decreased rate of LVEDD (ΔLVEDD) >10% or the increase rate of LVEF (ΔLVEF) >10%; the criteria of "no reversal" included LVEDD >50 mm for females or >55 mm for males and ΔLVEDD <10%, and LVEF <45% and ΔLVEF <10%. Results: Within the follow-up period, nine patients showed "complete reversal," eight "partial reversal," and nine "no reversal." Improvements in echocardiogram parameters were the most significant in "complete reversal" patients (P < 0.001), followed by "partial reversal" and "no reversal" patients (P < 0.05). The QRS (Q wave, R wave, S wave) duration and symptoms duration in "complete reversal" patients were the shortest, followed by "partial reversal" and "no reversal" patients. Conclusion: ACEIs or ARBs and BBs have a "complete reversal" effect on the left ventricular size and function of some FSIDCM patients. Patients with a narrow QRS and short symptom duration may have a good response.
RESUMEN
The role of long non-coding RNA (lncRNA) in endogenous cardiac regeneration remains largely elusive. The mammalian cardiomyocyte is capable of regeneration for a brief period after birth. This fact allows the exploration of the roles of critical lncRNAs in the regulation of cardiac regeneration. Through a cardiac regeneration model by apical resection (AR) of the left ventricle in neonatal mice, we identified an lncRNA named natriuretic peptide A antisense RNA 1 (NPPA-AS1), which negatively regulated cardiomyocyte proliferation. In neonates, NPPA-AS1 deletion did not affect heart development, but was sufficient to prolong the postnatal window of regeneration after AR. In adult mice, NPPA-AS1 deletion improved cardiac function and reduced infarct size after myocardial infarction (MI), associated with a significant improvement in cardiomyocyte proliferation. Further analysis showed that NPPA-AS1 interacted with DNA repair-related molecule splicing factor, proline- and glutamine-rich (SFPQ). A heteromer of SFPQ and non-POU domain-containing octamer-binding protein (NONO) was required for double-strand DNA break repair, but NPPA-AS1 was competitively bound with SFPQ due to the overlapped binding sites of SFPQ and NONO. NPPA-AS1 deletion promoted the binding of SFPQ-NONO heteromer, decreased DNA damage, and activated cardiomyocyte cell cycle re-entry. Together, loss of NPPA-AS1 promoted cardiomyocyte proliferation by stabilizing SFPQ-NONO heteromer-induced DNA repair and exerted a therapeutic effect against MI in adult mice. Consequently, NPPA-AS1 may be a novel target for stimulating cardiac regeneration to treat MI.
Asunto(s)
Infarto del Miocardio , ARN Largo no Codificante , Animales , Factor Natriurético Atrial , Proliferación Celular , Reparación del ADN , Proteínas de Unión al ADN , Mamíferos , Ratones , Infarto del Miocardio/genética , Miocitos Cardíacos , Procainamida/análogos & derivados , ARN Largo no Codificante/genética , Proteínas de Unión al ARN , RegeneraciónRESUMEN
Nonalcoholic fatty liver disease (NAFLD) is an emerging driver of cardiac arrhythmias. However, the relationship between NAFLD and malignant arrhythmia in non-ST-segment elevation myocardial infarction (NSTEMI) patients is still unclear.In this study, 358 NSTEMI inpatients were enrolled. They all received 24-hour Holter monitoring after percutaneous coronary intervention. All inpatients were divided into two groups: the non-NAFLD group (236 cases, 65.9%) and the NAFLD group (122 cases, 34.1%). Compared with the non-NAFLD group, the NAFLD group had a significantly higher incidence of PVCs/hour > 5 (premature ventricular complexes, 32.0% versus 9.3%, P < 0.001), ventricular tachycardia (VT, 22.1% versus 5.9%, P < 0.001), and sinus arrest (SA, 7.4% versus 1.3%, P = 0.002). We found that NAFLD was closely associated with the occurrence of VT [unadjusted odds ratio (OR) 4.507, 95% confidence interval (CI) 2.263-8.974, P < 0.001] and SA (OR 6.186, 95%CI 1.643-23.291, P = 0.007). After adjusting for age, sex, body mass index, and other confounding factors, the above differences were still statistically significant (VT: OR 4.808, 95%CI 2.254-10.253, P < 0.001; SA: OR 9.589, 95%CI 2.027-45.367, P = 0.004).NAFLD is associated with the occurrence of VT and SA in NSTEMI patients. It indicates that NAFLD might be a risk factor for malignant arrhythmias in post-NSTEMI patients.
Asunto(s)
Paro Cardíaco , Infarto del Miocardio sin Elevación del ST , Enfermedad del Hígado Graso no Alcohólico , Intervención Coronaria Percutánea , Infarto del Miocardio con Elevación del ST , Taquicardia Ventricular , Complejos Prematuros Ventriculares , Paro Cardíaco/complicaciones , Humanos , Infarto del Miocardio sin Elevación del ST/complicaciones , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Intervención Coronaria Percutánea/efectos adversos , Factores de Riesgo , Infarto del Miocardio con Elevación del ST/complicaciones , Taquicardia Ventricular/complicaciones , Taquicardia Ventricular/etiología , Complejos Prematuros Ventriculares/etiologíaRESUMEN
Acute myocardial infarction (MI) is one of the leading causes of death in humans. Our previous studies showed that gastrin alleviated acute myocardial ischaemia-reperfusion injury. We hypothesize that gastrin might protect against heart injury after MI by promoting angiogenesis. An MI model was simulated by ligating the anterior descending coronary artery in adult male C57BL/6J mice. Gastrin was administered twice daily by intraperitoneal injection for 2 weeks after MI. We found that gastrin reduced mortality, improved myocardial function with reduced infarct size and promoted angiogenesis. Gastrin increased HIF-1α and VEGF expression. Downregulation of HIF-1α expression by siRNA reduced the proliferation, migration and tube formation of human umbilical vein endothelial cells. These results indicate that gastrin restores cardiac function after MI by promoting angiogenesis via the HIF-1α/VEGF pathway.
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Gastrinas/farmacología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Infarto del Miocardio/tratamiento farmacológico , Neovascularización Patológica/prevención & control , Factor A de Crecimiento Endotelial Vascular/metabolismo , Animales , Proliferación Celular , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Infarto del Miocardio/patología , Transducción de Señal , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
The area under the blood pressure curve is associated with target organ damage, but accurately estimating its value is challenging. This study aimed to improve the utility of the area under the blood pressure curve to predict hypertensive target organ damage. This retrospective cohort study comprised of 634 consecutive patients with essential hypertension for >1 year. Target organ damage was defined as the presence of left ventricular hypertrophy and/or carotid artery plaques. We evaluated the associations between the cumulative blood pressure load, which was derived from ambulatory blood pressure monitoring data, and target organ damage. The predictive value of the cumulative blood pressure load for target organ damage was assessed using receiver operating characteristic curves. Left ventricular hypertrophy and carotid artery plaques were present in 392 (61.8%) and 316 (49.8%) patients, respectively. Patients with left ventricular hypertrophy and/or carotid artery plaques had higher 24-hour blood pressure, nocturnal cumulative systolic blood pressure, and nocturnal cumulative pulse pressure load. The nocturnal cumulative systolic blood pressure load was an independent predictor of left ventricular hypertrophy (odds ratio = 1.002, 95% confidence interval: 1.001-1.004; P = .000) and carotid artery plaques (odds ratio = 1.003, 95% confidence interval: 1.002-1.007; P = .007). The nocturnal cumulative systolic blood pressure and cumulative pulse pressure load, relative to mean blood pressure, were superior in predicting hypertensive target organ damage. Hence, the cumulative blood pressure load is a better indicator of blood pressure consequences, and the nocturnal cumulative systolic blood pressure and cumulative pulse pressure loads could predict target organ damage.