EFFETTI DELLA TERAPIA CON METOPROLOLO E SFINGOSINA 1 FOSFATO IN UN MODELLO SPERIMENTALE DI SCOMPENSO CARDIACO POST-ISCHEMICO

Un evento patologico chiave nello Scompenso Cardiaco (SC) è la disregolazione dei recettori β adrenergici cardiaci (βAR) conseguenza dell’iperattivazione da parte delle catecolammine. I beta bloccanti hanno effetti terapeutici nei pazienti con SC in quanto impediscono l’ulteriore down-regulation recettoriale. Sono comunque necessari ulteriori studi per approfondire al meglio i meccanismi d’azione di questa classe di farmaci. Inoltre è stato dimostrato che in corso di SC si assiste alla disregolazione del sistema recettoriale della sfingosina1fosfato (S1P), un fosfolipide bioattivo con effetti cardioprotettivi, nonostante i livelli circolanti di tale fosfolipide siano ridotti. È noto che in corso di scompenso, l’iperattivazione dei recettori β adrenergici cardiaci, da parte delle catecolammine, porta anche ad una downregulation del recettore di tipo 1 della S1P, favorendo la progressione della patologia. Il cross-talk tra questi due sistemi recettoriali sembra essere orchestrato da GRK2, che rappresenta il principale regolatore di questa interazione. Nel presente studio abbiamo osservato che il Metoprololo, β bloccante selettivo per il recettore β1, è in grado di prevenire la disfunzione del signaling della S1P rallentando la progressione dello scompenso cardiaco. Quindi è possibile ipotizzare che parte degli effetti benefici mediati dai beta bloccanti siano dovuti al miglioramento del signaling della S1P

βARKct gene-therapy improves β2-adrenergic receptor-dependent neoangiogenesis following hindlimb ischemia

Following hindlimb ischemia (HI) increased catecholamine levels within the ischemic muscle can cause dysregulation of β2-adrenergic receptor (β2AR) signaling leading to reduced revascularization. Indeed, in vivo β2AR overexpression, via gene therapy, enhances angiogenesis in a rat model of HI. G protein-coupled receptor kinase 2 (GRK2) is a key regulator of βAR signaling, and βARKct, a peptide inhibitor of GRK2, has been shown to prevent βAR down-regulation and to protect cardiac myocytes and stem cells from ischemic injury, through restoration of β2AR protective signaling (i.e. Akt/eNOS). Herein, we tested potential therapeutic effects of adenoviral-mediated βARKct gene transfer in an experimental model of HI and its effects on βAR signaling and on endothelial cell (EC) function in vitro. Accordingly, in this study, we surgically induced HI in rats by femoral artery resection (FAR). Fifteen days of ischemia resulted in significant βAR down-regulation that was paralleled by an about 2-fold increase in GRK2 levels in the ischemic muscle. Importantly, in vivo gene transfer of the βARKct in the hindlimb of rats at the time of FAR resulted in a marked improvement of hindlimb perfusion, with increased capillary and βAR density in the ischemic muscle, compared to control groups. The effect of βARKct expression was also assessed, in vitro in cultured ECs. Interestingly, in ECs expressing the βARKct, fenoterol, a β2AR-agonist, induced enhanced β2AR pro-angiogenic signaling and increased EC function. In conclusion, our results suggest that βARKct gene-therapy and subsequent GRK2 inhibition promotes angiogenesis in a model of HI by preventing ischemia-induced β2AR downregulation

Aldosterone and Mineralocorticoid Receptor System in Cardiovascular Physiology and Pathophysiology

The mineralocorticoid hormone aldosterone (Aldo) has been intensively studied for its ability to influence both the physiology and pathophysiology of the cardiovascular system. Indeed, although research on Aldo actions for decades has mainly focused on its effects in the kidney, several lines of evidence have now demonstrated that this hormone exerts disparate extrarenal adverse effects, especially in the circulatory system. Accordingly, in the last lusters, a number of studies in preclinical models (in vitro and in vivo) and in humans have established that Aldo, following the interaction with its receptor-the mineralocorticoid receptor (MR)-is able to activate specific intracellular genomic and nongenomic pathways, thus regulating the homeostasis of the cardiovascular system. Importantly, through this mechanism of action, this hormone becomes a crucial regulator of the function and growth of different types of cells, including fibroblasts, cardiomyocytes, and vascular cells. For this main reason, it is plausible that when Aldo is present at high levels in the blood, it profoundly modifies the physiology of these cells, therefore being at the foundation of several cardiovascular disorders, such as heart failure (HF). On these grounds, in this review, we will provide an updated account on the current knowledge concerning Aldo activity in the cardiovascular system and the most recent preclinical studies and clinical trials designed to test better approaches able to counter the hyperactivity of the Aldo/MR signaling pathway in the setting of cardiovascular diseases

Long-Term Caloric Restriction Improves Cardiac Function, Remodeling, Adrenergic Responsiveness, and Sympathetic Innervation in a Model of Postischemic Heart Failure

BACKGROUND: Caloric restriction (CR) has been described to have cardioprotective effects and improve functional outcomes in animal models and humans. Chronic ischemic heart failure (HF) is associated with reduced cardiac sympathetic innervation, dysfunctional β-adrenergic receptor signaling, and decreased cardiac inotropic reserve. We tested the effects of a long-term CR diet, started late after myocardial infarction on cardiac function, sympathetic innervation, and β-adrenergic receptor responsiveness in a rat model of postischemic HF. METHODS AND RESULTS: Adult male rats were randomly assigned to myocardial infarction or sham operation and 4 weeks later were further randomized to a 1-year CR or normal diet. One year of CR resulted in a significant reduction in body weight, heart weight, and heart weight/tibia length ratio when compared with normal diet in HF groups. At the end of the study period, echocardiography and histology revealed that HF animals under the CR diet had ameliorated left ventricular remodeling compared with HF rats fed with normal diet. Invasive hemodynamic showed a significant improvement of cardiac inotropic reserve in CR HF rats compared with HF-normal diet animals. Importantly, CR dietary regimen was associated with a significant increase of cardiac sympathetic innervation and with normalized cardiac β-adrenergic receptor levels in HF rats when compared with HF rats on the standard diet. CONCLUSIONS: We demonstrate, for the first time, that chronic CR, when started after HF established, can ameliorate cardiac dysfunction and improve inotropic reserve. At the molecular level, we find that chronic CR diet significantly improves sympathetic cardiac innervation and β-adrenergic receptor levels in failing myocardium

Development and Validation of a Scoring System That Includes Corrected QT Interval For Risk Analysis of Patients With Cirrhosis and Gastrointestinal Bleeding

The electrocardiographic QT interval is frequently prolonged in patients with cirrhosis. Acute gastrointestinal bleeding further prolongs corrected QT (QTc) in patients with cirrhosis, which has been associated with increased risk of death within 6 weeks. We aimed to confirm these findings and develop a mortality risk index that incorporates QTc

Prognostic Value of Lymphocyte G Protein-Coupled Receptor Kinase-2 Protein Levels in Patients With Heart Failure

Sympathetic nervous system hyperactivity is associated with poor prognosis in patients with heart failure (HF), yet routine assessment of sympathetic nervous system activation is not recommended for clinical practice. Myocardial G protein-coupled receptor kinase-2 (GRK2) is upregulated in HF patients, causing dysfunctional β-adrenergic receptor signaling. Importantly, myocardial GRK2 levels correlate with levels found in peripheral lymphocytes of HF patients