Emerging role of circulating piRNAs in the diagnosis of heart transplant rejection.

Background: Liquid biopsy offers a potential alternative to decrease or eliminate endomyocardial biopsy for diagnosing allograft rejection. p-element-induced wimpy testis-interacting RNAs (piRNAs) are novel and promising disease biomarkers for their intrinsic characteristics such as stability in body fluids; however, their role in allograft rejection remains unexplored.

Methods: A training set based on small RNA sequencing technology was performed to identify piRNAs in endomyocardial tissue (n = 8) and serum samples (n = 40) from patients following heart transplantation.

Transcriptomic Alterations in Spliceosome Components in Advanced Heart Failure: Status of Cardiac-Specific Alternative Splicing Factors.

Heart failure (HF) is associated with global changes in gene expression. Alternative mRNA splicing (AS) is a key regulatory mechanism underlying these changes. However, the whole status of molecules involved in the splicing process in human HF is unknown.

Circulating long non-coding RNAs detection after heart transplantation and its accuracy in the diagnosis of acute cardiac rejection.

Long non-coding RNAs (lncRNAs) are closely implicated in biological processes and diseases with high inflammatory components. These molecules exhibit significant temporal and tissue specificity. However, the expression and function of lncRNAs have not been studied in patients after heart transplantation.

Alterations in Mitochondrial Oxidative Phosphorylation System: Relationship of Complex V and Cardiac Dysfunction in Human Heart Failure.

Heart failure (HF) is a disease related to bioenergetic mitochondrial abnormalities. However, the whole status of molecules involved in the oxidative phosphorylation system (OXPHOS) is unknown. Therefore, we analyzed the OXPHOS transcriptome of human cardiac tissue by RNA-seq analyses (mRNA = 36; ncRNA = 30) in HF patients (ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM)) and control subjects.

Human recombinant relaxin-2 (serelaxin) regulates the proteome, lipidome, lipid metabolism and inflammatory profile of rat visceral adipose tissue.

Recombinant human relaxin-2 (serelaxin) has been widely proven as a novel drug with myriad effects at different cardiovascular levels, which support its potential therapeutic efficacy in several cardiovascular diseases (CVD). Considering these effects, together with the influence of relaxin-2 on adipocyte physiology and adipokine secretion, and the connection between visceral adipose tissue (VAT) dysfunction and the development of CVD, we could hypothesize that relaxin-2 may regulate VAT metabolism. Our objective was to evaluate the impact of a 2-week serelaxin treatment on the proteome and lipidome of VAT from Sprague-Dawley rats.

Plasma fibroblast activation protein is decreased in acute heart failure despite cardiac tissue upregulation.

Background: Cardiac fibroblast activation protein (FAP) has an emerging role in heart failure (HF). A paradoxical reduction in its levels in pathological conditions associated with acute processes has been observed. We aimed to identify FAP cardiac tissue expression and its relationship with the main cardiac fibrosis-related signaling pathways, and to compare plasma FAP levels in acute and chronic HF patients.

Combining Serum miR-144-3p and miR-652-3p as Potential Biomarkers for the Early Diagnosis and Stratification of Acute Cellular Rejection in Heart Transplantation Patients.

Background: There is a dire need for specific, noninvasive biomarkers that can accurately detect cardiac acute cellular rejection (ACR) early. Previously, we described miR-144-3p as an excellent candidate for detecting grade ≥2R ACR. Now, we investigated the combination of miR-144-3p with miR-652-3p, other differentially expressed serum miRNA we previously described, to improve diagnostic accuracy mainly in mild rejection to avoid reaching severe stages.

Altered MicroRNA Maturation in Ischemic Hearts: Implication of Hypoxia on XPO5 and DICER1 Dysregulation and RedoximiR State.

Ischemic cardiomyopathy (ICM) is associated with abnormal microRNA expression levels that involve an altered gene expression profile. However, little is known about the underlying causes of microRNA disruption in ICM and whether microRNA maturation is compromised. Therefore, we focused on microRNA maturation defects analysis and the implication of the microRNA biogenesis pathway and redox-sensitive microRNAs (redoximiRs).

The lipidomic and inflammatory profiles of visceral and subcutaneous adipose tissues are distinctly regulated by the SGLT2 inhibitor empagliflozin in Zucker diabetic fatty rats.

The pharmacological inhibition of sodium-glucose cotransporter 2 (SGLT2) has emerged as a treatment for patients with type 2 diabetes mellitus (T2DM), cardiovascular disease and/or other metabolic disturbances, although some of the mechanisms implicated in their beneficial effects are unknown. The SGLT2 inhibitor (SGLT2i) empagliflozin has been suggested as a regulator of adiposity, energy metabolism, and systemic inflammation in adipose tissue. The aim of our study was to evaluate the impact of a 6-week-empagliflozin treatment on the lipidome of visceral (VAT) and subcutaneous adipose tissue (SAT) from diabetic obese Zucker Diabetic Fatty (ZDF) rats using an untargeted metabolomics approach.

Relaxin-2 plasma levels in atrial fibrillation are linked to inflammation and oxidative stress markers.

Relaxin-2 exerts many favourable cardiovascular effects in pathological circumstances such as atrial fibrillation (AF) and heart failure, but the mechanisms underlying its actions are not completely understood. Since inflammation and fibrosis are pivotal processes in the pathogenesis of AF, our aim was to study the relationship between relaxin-2 plasma levels in left atrium (LA) and peripheral vein with molecules implicated in fibrosis, inflammation and oxidative stress in AF patients, and to evaluate the anti-fibrotic ability of relaxin-2 in normal human atrial cardiac fibroblasts (NHCF-A). Peripheral vein relaxin-2 plasma levels were higher than LA relaxin-2 plasma levels in men while, in women, peripheral vein relaxin-2 levels were increased compared to men.

Cardiac Sodium/Hydrogen Exchanger (NHE11) as a Novel Potential Target for SGLT2i in Heart Failure: A Preliminary Study.

Despite the reduction of cardiovascular events, including the risk of death, associated with sodium/glucose cotransporter 2 inhibitors (SGLT2i), their basic action remains unclear. Sodium/hydrogen exchanger (NHE) has been proposed as the mechanism of action, but there are controversies related to its function and expression in heart failure (HF). We hypothesized that sodium transported-related molecules could be altered in HF and modulated through SGLT2i.

Alpha-cardiac Actin Serum Expression Levels Detect Acute Cellular Rejection in Heart Transplant Patients.

Background: Given the central role of sarcomeric dysfunction in cardiomyocyte biology and sarcomere alterations described in endomyocardial biopsies of transplant patients with rejection, we hypothesized that the serum expression levels of genes encoding sarcomeric proteins were altered in acute cellular rejection (ACR). The aim of this study is to identify altered sarcomere-related molecules in serum and to evaluate their diagnostic accuracy for detecting rejection episodes.

Methods: Serum samples from transplant recipients undergoing routine endomyocardial biopsies were included in an RNA sequencing analysis (n = 40).

Relaxin-2 as a Potential Biomarker in Cardiovascular Diseases.

The pleiotropic hormone relaxin-2 plays a pivotal role in the physiology and pathology of the cardiovascular system. Relaxin-2 exerts relevant regulatory functions in cardiovascular tissues through the specific receptor relaxin family peptide receptor 1 (RXFP1) in the regulation of cardiac metabolism; the induction of vasodilatation; the reversion of fibrosis and hypertrophy; the reduction of inflammation, oxidative stress, and apoptosis; and the stimulation of angiogenesis, with inotropic and chronotropic effects as well. Recent preclinical and clinical outcomes have encouraged the potential use of relaxin-2 (or its recombinant form, known as serelaxin) as a therapeutic strategy during cardiac injury and/or in patients suffering from different cardiovascular disarrangements, especially heart failure.

Cardiac Allograft Rejection Induces Changes in Nucleocytoplasmic Transport: RANGAP1 as a Potential Non-Invasive Biomarker.

The non-invasive diagnosis of acute cellular rejection (ACR) is a major challenge. We performed a molecular study analyzing the predictive capacity of serum RanGTPase AP1 (RANGAP1) for diagnosing ACR during the first year after heart transplantation (HT). We included the serum samples of 75 consecutive HT patients, extracted after clinical stability, to determine the RANGAP1 levels through ELISA.

Role of Sodium-Glucose Co-Transporter 2 Inhibitors in the Regulation of Inflammatory Processes in Animal Models.

Sodium-glucose co-transporter 2 inhibitors, also known as gliflozins, were developed as a novel class of anti-diabetic agents that promote glycosuria through the prevention of glucose reabsorption in the proximal tubule by sodium-glucose co-transporter 2. Beyond the regulation of glucose homeostasis, they resulted as being effective in different clinical trials in patients with heart failure, showing a strong cardio-renal protective effect in diabetic, but also in non-diabetic patients, which highlights the possible existence of other mechanisms through which gliflozins could be exerting their action. So far, different gliflozins have been approved for their therapeutic use in T2DM, heart failure, and diabetic kidney disease in different countries, all of them being diseases that have in common a deregulation of the inflammatory process associated with the pathology, which perpetuates and worsens the disease.

DNMT3B System Dysregulation Contributes to the Hypomethylated State in Ischaemic Human Hearts.

A controversial understanding of the state of the DNA methylation machinery exists in ischaemic cardiomyopathy (ICM). Moreover, its relationship to other epigenetic alterations is incomplete. Therefore, we carried out an in-depth study of the DNA methylation process in human cardiac tissue.

Electron Microscopy Reveals Evidence of Perinuclear Clustering of Mitochondria in Cardiac Biopsy-Proven Allograft Rejection.

Acute cellular rejection is a major complication in heart transplantation. We focus on the analysis of new ultrastructural findings in cardiac biopsy rejection based on mitochondrial intracellular organization. This study includes heart transplanted patients from a single center who were referred for endomyocardial biopsies as a scheduled routine screening.

The Treatment With the SGLT2 Inhibitor Empagliflozin Modifies the Hepatic Metabolome of Male Zucker Diabetic Fatty Rats Towards a Protective Profile.

The EMPA-REG OUTCOME (Empagliflozin, Cardiovascular Outcome Event Trial in patients with Type 2 Diabetes Mellitus (T2DM)) trial evidenced the potential of sodium-glucose cotransporter 2 (SGLT2) inhibitors for the treatment of patients with diabetes and cardiovascular disease. Recent evidences have shown the benefits of the SGLT2 inhibitor empagliflozin on improving liver steatosis and fibrosis in patients with T2DM. Metabolomic studies have been shown to be very useful to improve the understanding of liver pathophysiology during the development and progression of metabolic hepatic diseases, and because the effects of empagliflozin and of other SGLT2 inhibitors on the complete metabolic profile of the liver has never been analysed before, we decided to study the impact on the liver of male Zucker diabetic fatty (ZDF) rats of a treatment for 6 weeks with empagliflozin using an untargeted metabolomics approach, with the purpose to help to clarify the benefits of the use of empagliflozin at hepatic level.

Implication of Sphingolipid Metabolism Gene Dysregulation and Cardiac Sphingosine-1-Phosphate Accumulation in Heart Failure.

Disturbances in sphingolipid metabolism lead to biological function dysregulation in many diseases, but it has not been described in heart failure (HF). Sphingosine-1-phosphate (S1P) levels have not ever been measured in the myocardium. Therefore, we analyze the gene dysregulation of human cardiac tissue by mRNA-seq ( = 36) and ncRNA-seq ( = 50).

Diagnostic value of serum miR-144-3p for the detection of acute cellular rejection in heart transplant patients.

Background: The development of noninvasive approaches for the early diagnosis of acute cellular rejection (ACR), an important complication of cardiac transplantation, is of great importance in clinical practice. We conducted a nontargeted transcriptomic study focused on identifying serum miRNAs to evaluate their diagnostic accuracy for detecting rejection episodes.

Methods: We included consecutive serum samples from transplant recipients undergoing routine endomyocardial biopsies.

Value of SERCA2a as a Biomarker for the Identification of Patients with Heart Failure Requiring Circulatory Support.

Background: Heart failure (HF) alters the nucleo-cytoplasmic transport of cardiomyocytes and reduces SERCA2a levels, essential for intracellular calcium homeostasis. We consider in this study whether the molecules involved in these processes can differentiate those patients with advanced HF and the need for mechanical circulatory support (MCS) as a bridge to recovery or urgent heart transplantation from those who are clinically stable and who are transplanted in an elective code.

Material And Method: Blood samples from 29 patients with advanced HF were analysed by ELISA, and the plasma levels of Importin5, Nucleoporin153 kDa, RanGTPase-Activating Protein 1 and sarcoplasmic reticulum Ca ATPase were compared between patients requiring MCS and those patients without a MCS need prior to heart transplantation.

Alterations in the Nucleocytoplasmic Transport in Heart Transplant Rejection.

Background: Nucleocytoplasmic transport is a crucial process for cell function. Previous studies have observed alterations in different molecules involved in it, relating them to ventricular function. However, there are no published data evaluating possible differences in the expression of these molecules in heart transplantation (HT) recipients.

Relaxin has beneficial effects on liver lipidome and metabolic enzymes.

Relaxin is an insulin-like hormone with pleiotropic protective effects in several organs, including the liver. We aimed to characterize its role in the control of hepatic metabolism in healthy rats. Sprague-Dawley rats were treated with human recombinant relaxin-2 for 2 weeks.

Plasma Levels of SERCA2a as a Noninvasive Biomarker of Primary Graft Dysfunction After Heart Transplantation.

Background: Noninvasive detection of primary graft dysfunction (PGD) remains a major challenge. SERCA2a plays an important role in cardiac homeostasis and its dysregulation has been associated with ventricular dysfunction and rejection. This study aimed to determine the potential utility of plasma levels of SERCA2a as a biomarker of PGD.