RESUMO
Pulmonary arterial hypertension (PAH) is a chronic disorder characterized by excessive pulmonary vascular remodeling, leading to elevated pulmonary vascular resistance and right ventricle (RV) overload and failure. MicroRNA-146a (miR-146a) promotes vascular smooth muscle cell proliferation and vascular neointimal hyperplasia, both hallmarks of PAH. This study aimed to investigate the effects of miR-146a through pharmacological or genetic inhibition on experimental PAH and RV pressure overload animal models. Additionally, we examined the overexpression of miR-146a on human pulmonary artery smooth muscle cells (hPASMCs). Here, we showed that miR-146a genic expression was increased in the lungs of patients with PAH and the plasma of monocrotaline (MCT) rats. Interestingly, genetic ablation of miR-146a improved RV hypertrophy and systolic pressures in Sugen 5415/hypoxia (SuHx) and pulmonary arterial banding (PAB) mice. Pharmacological inhibition of miR-146a improved RV remodeling in PAB-wild type mice and MCT rats, and enhanced exercise capacity in MCT rats. However, overexpression of miR-146a did not affect proliferation, migration, and apoptosis in control-hPASMCs. Our findings show that miR-146a may play a significant role in RV function and remodeling, representing a promising therapeutic target for RV hypertrophy and, consequently, PAH.
Assuntos
MicroRNAs , Hipertensão Arterial Pulmonar , Artéria Pulmonar , Função Ventricular Direita , Animais , MicroRNAs/genética , MicroRNAs/metabolismo , Ratos , Humanos , Camundongos , Masculino , Hipertensão Arterial Pulmonar/genética , Hipertensão Arterial Pulmonar/metabolismo , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Modelos Animais de Doenças , Monocrotalina , Proliferação de Células/genética , Miócitos de Músculo Liso/metabolismo , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/fisiopatologia , Hipertrofia Ventricular Direita/genética , Hipertrofia Ventricular Direita/fisiopatologia , Hipertrofia Ventricular Direita/metabolismo , Remodelação Vascular/genética , Ratos Sprague-DawleyRESUMO
Obesity is among the most common chronic disorders, worldwide. It is a complex disease that reflects the interactions between environmental influences, multiple genetic allelic variants, and behavioral factors. Recent developments have also shown that biological conditions in utero play an important role in the programming of energy homeostasis systems and might have an impact on obesity and metabolic disease risk. The corticotropin-releasing hormone (CRH) family of neuropeptides, as a central element of energy homeostasis, has been evaluated for its role in the pathophysiology of obesity. This review aims to summarize the relevance and effects of the CRH family of peptides in the pathophysiology of obesity spanning from fetal life to adulthood.
Assuntos
Hormônio Liberador da Corticotropina , Obesidade , Humanos , Hormônio Liberador da Corticotropina/metabolismo , Obesidade/metabolismo , Gravidez , Feminino , Metabolismo Energético/fisiologia , Adulto , Efeitos Tardios da Exposição Pré-Natal , Homeostase/fisiologiaRESUMO
Pulmonary hypertension (PH) is a progressive condition that affects the pulmonary vessels, but its main prognostic factor is the right ventricle (RV) function. Many mice/rat models are used for research in PAH, but results fail to translate to clinical trials. This study reviews studies that test interventions on pulmonary artery banding (PAB), a model of isolated RV disfunction, and PH models. Multiple tested drugs both improved pulmonary vascular hemodynamics in PH models and improved RV structure and function in PAB animals. PH models and PAB animals frequently exhibited similar results (73.1% concordance). Macitentan, sildenafil, and tadalafil improved most tested pathophysiological parameters in PH models, but almost none in PAB animals. Results are frequently not consistent with other studies, possibly due to the methodology, which greatly varied. Some research groups start treating the animals immediately, and others wait up to 4 weeks from model induction. Treatment duration and choice of anaesthetic are other important differences. This review shows that many drugs currently under research for PAH have a cardioprotective effect on animals that may translate to humans. However, a uniformization of methods may increase comparability between studies and, thus, improve translation to clinical trials.
Assuntos
Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Humanos , Camundongos , Ratos , Animais , Hipertensão Arterial Pulmonar/tratamento farmacológico , Função Ventricular Direita , Artéria Pulmonar , Hipertensão Pulmonar Primária Familiar , Hipertensão Pulmonar/tratamento farmacológico , Modelos Animais de DoençasRESUMO
The hormone relaxin-2 has emerged as a promising player in regulating the physiology of the cardiovascular system. Through binding to the relaxin family peptide receptor 1 (RXFP1), this hormone elicits multiple physiological responses including vasodilation induction, reduction of inflammation and oxidative stress, and angiogenesis stimulation. The role of relaxin-2, or its recombinant human form known as serelaxin, has been investigated in preclinical and clinical studies as a potential therapy for cardiovascular diseases, especially heart failure, whose current therapy is still unoptimized. However, evidence from past clinical trials has been inconsistent and further research is needed to fully understand the potential applications of relaxin-2. This review provides an overview of serelaxin use in clinical trials and discusses future directions in the development of relaxin-2 mimetics, which may offer new therapeutic options for patients with heart failure.
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Recent evidence suggests that vitamin D is involved in the development of pulmonary arterial hypertension (PAH). The aim of this study was to analyze the electrophysiological and contractile properties of pulmonary arteries (PAs) in vitamin D receptor knockout mice (Vdr-/-). PAs were dissected and mounted in a wire myograph. Potassium membrane currents were recorded in freshly isolated PA smooth muscle cells (PASMCs) using the conventional whole-cell configuration of the patch-clamp technique. Potential vitamin D response elements (VDREs) in Kv7 channels coding genes were studied, and their protein expression was analyzed. Vdr-/- mice did not show a pulmonary hypertensive phenotype, as neither right ventricular hypertrophy nor endothelial dysfunction was apparent. However, resistance PA from these mice exhibited increased response to retigabine, a Kv7 activator, compared to controls and heterozygous mice. Furthermore, the current sensitive to XE991, a Kv7 inhibitor, was also higher in PASMCs from knockout mice. A possible VDRE was found in the gene coding for KCNE4, the regulatory subunit of Kv7.4. Accordingly, Vdr-/- mice showed an increased expression of KCNE4 in the lungs, with no changes in Kv7.1 and Kv7.4. These results indicate that the absence of Vdr in mice, as occurred with vitamin D deficient rats, is not sufficient to induce PAH. However, the contribution of Kv7 channel currents to the regulation of PA tone is increased in Vdr-/- mice, resembling animals and humans suffering from PAH.
Assuntos
Canais de Potássio de Abertura Dependente da Tensão da Membrana , Artéria Pulmonar , Animais , Humanos , Camundongos , Ratos , Canais de Potássio KCNQ/metabolismo , Camundongos Knockout , Músculo Liso Vascular/metabolismo , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Artéria Pulmonar/metabolismo , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Vitamina D/farmacologia , Vitamina D/metabolismoRESUMO
Potassium channel subfamily K member 3 (KCNK3), encoded by the KCNK3 gene, is part of the two-pore domain potassium channel family, constitutively active at resting membrane potentials in excitable cells, including smooth muscle and cardiac cells. Several physiological and pharmacological mediators, such as intracellular signalling pathways, extracellular pH, hypoxia and anaesthetics, regulate KCNK3 channel function. Recent studies show that modulation of KCNK3 channel expression and function strongly influences pulmonary vascular cell and cardiomyocyte function. The altered activity of KCNK3 in pathological situations such as atrial fibrillation, pulmonary arterial hypertension and right ventricular dysfunction demonstrates the crucial role of KCNK3 in cardiovascular homeostasis. Furthermore, loss of function variants of KCNK3 have been identified in patients suffering from pulmonary arterial hypertension and atrial fibrillation. This review focuses on current knowledge of the role of the KCNK3 channel in pulmonary circulation and the heart, in healthy and pathological conditions.
Assuntos
Fibrilação Atrial , Canais de Potássio de Domínios Poros em Tandem , Hipertensão Arterial Pulmonar , Humanos , Circulação Pulmonar , Fibrilação Atrial/genética , Fibrilação Atrial/metabolismo , Potenciais da Membrana , Pulmão/metabolismo , Canais de Potássio de Domínios Poros em Tandem/metabolismoRESUMO
Prevalence of congenital heart diseases worldwide is around 9 per 1000 newborns, 20% of which affect the pulmonary valve or right ventricular outflow tract. As survival after surgical repair of these defects has improved over time, there is the need to address the long-term issues of older children and young adults with "repaired" congenital heart diseases. In recent decades, the most used types of valves are the mechanical and bioprosthetic valves. Despite improving patients' quality of life, these effects are suboptimal due to their limitations, such as the inability to grow and adapt to hemodynamic changes. These issues have led to the search for living valve solutions through tissue engineering to respond to these challenges. This article aims to review the performance of traditional pulmonary valves and understand how tissue engineering-based valves can improve the management of these patients.
Assuntos
Bioprótese , Cardiopatias Congênitas , Implante de Prótese de Valva Cardíaca , Próteses Valvulares Cardíacas , Valva Pulmonar , Recém-Nascido , Criança , Adulto Jovem , Humanos , Adolescente , Valva Pulmonar/cirurgia , Engenharia Tecidual , Qualidade de Vida , Resultado do Tratamento , Cardiopatias Congênitas/cirurgiaRESUMO
While guidelines for management of heart failure with reduced ejection fraction (HFrEF) are consensual and have led to improved survival, treatment options for heart failure with preserved ejection fraction (HFpEF) remain limited and aim primarily for symptom relief and improvement of quality of life. Due to the shortage of therapeutic options, several drugs have been investigated in multiple clinical trials. The majority of these trials have reported disappointing results and have suggested that HFpEF might not be as simply described by ejection fraction as previously though. In fact, HFpEF is a complex clinical syndrome with various comorbidities and overlapping distinct phenotypes that could benefit from personalized therapeutic approaches. This review summarizes the results from the most recent phase III clinical trials for HFpEF and the most promising drugs arising from phase II trials as well as the various challenges that are currently holding back the development of new pharmacotherapeutic options for these patients.
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Insuficiência Cardíaca , Humanos , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/epidemiologia , Volume Sistólico , Qualidade de Vida , ComorbidadeRESUMO
BACKGROUND: Heart failure (HF) is a high prevalent syndrome with significant burden worldwide. B-type natriuretic peptide (BNP) and N-terminal proBNP are the gold standard biomarkers in HF management. Although useful in clinical practice, they have limitations as their expression can be influenced by ventricular function, aging, obesity, renal failure and atrial arrhythmias. MicroRNAs have recently emerged as potential diagnostic and prognostic biomarkers, given that they are related to cell growth, proliferation, differentiation, and metabolism. An increasing amount of research has highlighted some microRNAs for their potential as HF biomarkers. However, different study designs, methods and study groups have led to inconsistent results. METHODS AND RESULTS: We performed a systematic search of available literature on Pubmed and Scopus reporting the prognostic value of microRNAs in HF, followed by a review of risk of bias, according to Quadas Group Standards. Simultaneously, microRNAs' potential as differential diagnosis and severity biomarkers was also analyzed. Studies have described circulating microRNA as potential diagnostic, prognostic, and severity markers. Mir-622, -519 and -499 were significantly related to HF with reduced ejection fraction, whereas miR-22-3p revealed greater ability as a severity biomarker. Let-7i-5p, miR-223-5p, miR-423-5p, miR-21, miR-1306-5p and miR-122 serum expressions presented a consistent correlation with HF prognosis. Furthermore, identified miR targets were associated with signaling pathways already known to be involved in HF progression. CONCLUSION: Several miRs were related to HF pathophysiology and demonstrated potential as biomarkers for disease progression. MicroRNAs have a promising role in HF, and although unquestionable, we require a deeper and broader understanding of their role and function for future research.
Assuntos
MicroRNA Circulante , Insuficiência Cardíaca , MicroRNAs , Biomarcadores , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Peptídeo Natriurético Encefálico , PrognósticoAssuntos
Células Artificiais , Cardiologia , Inteligência Artificial , Previsões , Aprendizado de MáquinaRESUMO
Pulmonary arterial hypertension (PAH), also known as Group 1 Pulmonary Hypertension (PH), is a PH subset characterized by pulmonary vascular remodeling and pulmonary arterial obstruction. PAH has an estimated incidence of 15-50 people per million in the United States and Europe, and is associated with high mortality and morbidity, with patients' survival time after diagnosis being only 2.8 years. According to current guidelines, right heart catheterization is the gold standard for diagnostic and prognostic evaluation of PAH patients. However, this technique is highly invasive, so it is not used in routine clinical practice or patient follow-up. Thereby, it is essential to find new non-invasive strategies for evaluating disease progression. Biomarkers can be an effective solution for determining PAH patient prognosis and response to therapy, and aiding in diagnostic efforts, so long as their detection is non-invasive, easy, and objective. This review aims to clarify and describe some of the potential new candidates as circulating biomarkers of PAH.
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Endothelial dysfunction is a key player in advancing vascular pathology in pulmonary arterial hypertension (PAH), a disease essentially characterized by intense remodeling of the pulmonary vasculature, vasoconstriction, endothelial dysfunction, inflammation, oxidative stress, and thrombosis in situ. These vascular features culminate in an increase in pulmonary vascular resistance, subsequent right heart failure, and premature death. Over the past years, there has been a great development in our understanding of pulmonary endothelial biology related to the genetic and molecular mechanisms that modulate the endothelial response to direct or indirect injury and how their dysregulation can promote PAH pathogenesis. Ion channels are key regulators of vasoconstriction and proliferative/apoptotic phenotypes; however, they are poorly studied at the endothelial level. The current review will describe and categorize different expression, functions, regulation, and remodeling of endothelial ion channels (K+, Ca2+, Na+, and Cl- channels) in PAH. We will focus on the potential pathogenic role of ion channel deregulation in the onset and progression of endothelial dysfunction during the development of PAH and its potential therapeutic role.
Assuntos
Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Doenças Vasculares , Humanos , Hipertensão Pulmonar/patologia , Canais Iônicos/genética , Canais Iônicos/metabolismo , VasoconstriçãoRESUMO
The urocortins (Ucns) belong to the corticotropin-releasing factor (CRF) family of peptides and have multiple effects within the central nervous and the cardiovascular systems. With growing evidence indicating significant cardioprotective properties and cardiovascular actions of these peptides, the question arises as to whether the plasma profiles of the Ucns are altered in pathologic settings. While reports have shown conflicting results and findings have not been corroborated in multiple independent cohorts, it seems likely that plasma Ucn concentrations are elevated in multiple cardiovascular conditions. The degree of increase and accurate determination of circulating values of the Ucns requires further validation.
Assuntos
Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Urocortinas/sangue , Animais , HumanosRESUMO
Background: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by increased pulmonary artery pressure leading to right ventricular (RV) failure. While current PAH therapies improve patient outlook, they show limited benefit in attenuating RV dysfunction. Recent investigations demonstrated that the thromboxane (TX) A2 receptor (TP) antagonist NTP42 attenuates experimental PAH across key hemodynamic parameters in the lungs and heart. This study aimed to validate the efficacy of NTP42:KVA4, a novel oral formulation of NTP42 in clinical development, in preclinical models of PAH while also, critically, investigating its direct effects on RV dysfunction. Methods: The effects of NTP42:KVA4 were evaluated in the monocrotaline (MCT) and pulmonary artery banding (PAB) models of PAH and RV dysfunction, respectively, and when compared with leading standard-of-care (SOC) PAH drugs. In addition, the expression of the TP, the target for NTP42, was investigated in cardiac tissue from several other related disease models, and from subjects with PAH and dilated cardiomyopathy (DCM). Results: In the MCT-PAH model, NTP42:KVA4 alleviated disease-induced changes in cardiopulmonary hemodynamics, pulmonary vascular remodeling, inflammation, and fibrosis, to a similar or greater extent than the PAH SOCs tested. In the PAB model, NTP42:KVA4 improved RV geometries and contractility, normalized RV stiffness, and significantly increased RV ejection fraction. In both models, NTP42:KVA4 promoted beneficial RV adaptation, decreasing cellular hypertrophy, and increasing vascularization. Notably, elevated expression of the TP target was observed both in RV tissue from these and related disease models, and in clinical RV specimens of PAH and DCM. Conclusion: This study shows that, through antagonism of TP signaling, NTP42:KVA4 attenuates experimental PAH pathophysiology, not only alleviating pulmonary pathologies but also reducing RV remodeling, promoting beneficial hypertrophy, and improving cardiac function. The findings suggest a direct cardioprotective effect for NTP42:KVA4, and its potential to be a disease-modifying therapy in PAH and other cardiac conditions.
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Urocortin (Ucn)-2 has shown promising therapeutic effects on heart failure (HF). However, there are still significant knowledge gaps regarding the role and modulation of the endogenous Ucn-2 axis in the cardiovascular system and, specifically, in acute HF. We evaluated Ucn-2 levels in admission serum samples of 80 acute HF patients and assessed their association with clinical, analytical and echocardiographic parameters. Median age was 76.5 years, and 37 patients (46%) were male. Median serum Ucn-2 was 2.3ng/mL. Ucn-2 levels were positively associated with peripheral edemas (Pâ¯=â¯0.022), hepatomegaly (Pâ¯=â¯0.007) and sodium retention score (ρâ¯=â¯0.37, Pâ¯=â¯0.001) and inversely correlated with inferior vena cava collapse at inspiration (ρâ¯=â¯-0.37, Pâ¯=â¯0.001). Additionally, patients with higher Ucn-2 levels had a higher prevalence of right atrial dilation (Pâ¯=â¯0.027), right ventricle dilation (Pâ¯=â¯0.008), and higher systolic pulmonary artery pressure (ρâ¯=â¯0.34, Pâ¯=â¯0.002). Regarding analytical parameters, Ucn-2 correlated positively with log BNP (râ¯=â¯0.22, Pâ¯=â¯0.055) and inversely with uric acid (râ¯=â¯0.24, Pâ¯=â¯0.029) and total (râ¯=â¯-0.30, Pâ¯=â¯0.007) and low-density lipoprotein cholesterol (râ¯=â¯-0.23, Pâ¯=â¯0.038). No associations were found between Ucn-2 and age, sex or left heart structure or function. In conclusion, Circulating Ucn-2 was associated with clinical and echocardiographic markers of volume overload and pulmonary hypertension in acute HF patients.
Assuntos
Insuficiência Cardíaca , Hipertensão Pulmonar , Idoso , Biomarcadores , Ecocardiografia , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/diagnóstico , Humanos , Hipertensão Pulmonar/diagnóstico , Masculino , UrocortinasRESUMO
Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent and intractable form of cardiac decompensation commonly associated with diastolic dysfunction. Here, we show that diastolic dysfunction in patients with HFpEF is associated with a cardiac deficit in nicotinamide adenine dinucleotide (NAD+). Elevating NAD+ by oral supplementation of its precursor, nicotinamide, improved diastolic dysfunction induced by aging (in 2-year-old C57BL/6J mice), hypertension (in Dahl salt-sensitive rats), or cardiometabolic syndrome (in ZSF1 obese rats). This effect was mediated partly through alleviated systemic comorbidities and enhanced myocardial bioenergetics. Simultaneously, nicotinamide directly improved cardiomyocyte passive stiffness and calcium-dependent active relaxation through increased deacetylation of titin and the sarcoplasmic reticulum calcium adenosine triphosphatase 2a, respectively. In a long-term human cohort study, high dietary intake of naturally occurring NAD+ precursors was associated with lower blood pressure and reduced risk of cardiac mortality. Collectively, these results suggest NAD+ precursors, and especially nicotinamide, as potential therapeutic agents to treat diastolic dysfunction and HFpEF in humans.