0000000000360021
AUTHOR
Jaime Agüero
Myocardial and Peripheral Lymphocytic Transcriptomic Dissociation of β-adrenoceptors and G Protein–coupled Receptor Kinases in Heart Transplantation
Background The genetic expression of adrenergic receptors plays an important pathophysiologic role in heart failure. G protein–coupled receptor kinases (GRKs) desensitize the β-receptor to catecholaminergic stimulation. It has been suggested that their mRNA expression in peripheral lymphocytes could mirror the changes in their myocardial expression in the failing heart, but this relationship between the myocyte and lymphocyte has not been studied in heart transplantation (HT). The objective of this study was to analyze adrenergic receptor and GRK mRNA expression in myocardium and lymphocytes and their correlation. Methods Twenty-three HT patients without evidence of acute rejection or echoc…
Myocardial and lymphocytic expression of eNOS and nNOS before and after heart transplantation: Relationship to clinical status
Abstract Aims The present study investigates the expression and clinical relevance of the constitutive NO synthases in heart and peripheral blood mononuclear cells (PBMCs) obtained from heart failure patients. Main methods mRNA and protein levels (qRT-PCR and immunoblot) of eNOS and nNOS were determined in: i) Left ventricle (LV, n = 4) and PBMCs (n = 10) from healthy donors; ii) LV, right ventricle (RV) and PBMCs of heart failure (HF) patients (n = 32); and iii) biopsies and PBMCs of the HF patients after cardiac transplant (n = 15). Key findings Expression of constitutive NOS isoforms in heart exhibits wide variability in HF patients, but this variability was not related to aetiology, dis…
Different expression of adrenoceptors and GRKs in the human myocardium depends on heart failure etiology and correlates to clinical variables.
Downregulation of β1- adrenergic receptors (β1-ARs) and increased expression/function of G-protein-coupled receptor kinase 2 (GRK2) have been observed in human heart failure, but changes in expression of other ARs and GRKs have not been established. Another unresolved question is the incidence of these compensatory mechanisms depending on heart failure etiology and treatment. To analyze these questions, we quantified the mRNA/protein expressions of six ARs (α1A, α1B, α1D, β1, β2, and β3) and three GRKs (GRK2, GRK3, and GRK5) in left (LV) and right ventricle (RV) from four donors, 10 patients with ischemic cardiomyopathy (IC), 14 patients with dilated cardiomyopathy (DC), and 10 patients wit…
Clinical Predictors of Immunotolerance in Heart Transplantation
Abstract Background and Aim The drugs routinely administered to prevent rejection often cause lethal side effects. Tolerant patients, therefore, should be identified to minimize these problems. The aim of this analysis was to identify clinical variables that may be associated with tolerance. Methods We recruited 522 heart transplants (HT), excluding combined procedures, retransplantations, pediatric recipients, and subjects who died in the first year to obtain a cohort of 375 patients. Two groups were distinguished by the presence of echocardiographic, clinical, or pathological evidence of rejection in the first year (15 echocardiograms and 10 protocol biopsies per patient); 99 tolerant pat…
β2- and β1-Adrenoceptor Expression Exhibits a Common Regulatory Pattern With GRK2 and GRK5 in Human and Animal Models of Cardiovascular Diseases.
To explore if genic expression of β(1)- or β(2)-adrenoceptors (ARs) exhibits a common regulatory pattern with G protein-coupled receptor kinase (GRK) 2, GRK3, or GRK5 expression, we determined messenger RNA levels for these genes in different tissues from human and animal models of cardiovascular disease. We measured genic expression by qRT polymerase chain reaction in the left and right ventricles or peripheral blood mononuclear cells from healthy (n = 21), hypertensive (n = 20), heart failure (n = 24), and heart transplanted patients (n = 17) or in left ventricle, peripheral blood mononuclear cells, and kidney from spontaneously hypertensive rats or L-N-methyl-arginine-induced hypertensiv…
Myocardial G Protein Receptor–Coupled Kinase Expression Correlates With Functional Parameters and Clinical Severity in Advanced Heart Failure
In heart failure (HF), sympathetic hyperactivation induces deleterious effects in myocardial β-adrenergic signaling, with receptor down-regulation and desensitization mediated by G protein receptor-coupled kinases (GRKs). We hypothesised that changes in GRK isoforms may be associated with clinical status in advanced HF, using the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) scale.We included 31 patients with advanced HF undergoing transplantation. According to INTERMACS profiles, mRNA and protein levels of GRK isoforms in left ventricular (LV) myocardium were analyzed and compared with nonfailing LV samples.In failing LV myocardium, GRK2 and GRK5 (but not G…
Activation of α1A-adrenoceptors desensitizes the rat aorta response to phenylephrine through a neuronal NOS pathway, a mechanism lost with ageing
Background and purpose A NO-mediated desensitization of vasoconstrictor responses evoked by stimulation of α1 -adrenoceptors has been reported in different vessels. We investigated the involvement of each α1 -adrenoceptor subtype and constitutive NOS isoforms and the influence of ageing and hypertension on this process. Experimental approach Wistar and spontaneously hypertensive rats (SHR), 16, 32, 52 and 72 weeks-old, were used to evaluate the desensitization process. Expression of α1 -adrenoceptor subtypes, endothelial NOS (eNOS) and neuronal NOS (nNOS) were determined in rat aorta and left ventricle (LV). Expression levels were also evaluated in LV of a group of heart failure patients wi…