Inhibition of Let-7 microRNA attenuates myocardial remodeling and improves cardiac function postinfarction in mice

Peer reviewe

Downregulation of G protein-coupled receptor kinase 2 levels enhances cardiac insulin sensitivity and switches on cardioprotective gene expression patterns

G protein-coupled receptor kinase 2 (GRK2) has recently emerged as a negative modulator of insulin signalling. GRK2 downregulation improves insulin sensitivity and prevents systemic insulin resistance (IR). Cardiac GRK2 levels are increased in 5 human heart failure, while genetically inhibiting GRK2 leads to cardioprotection in mice. However, the molecular basis underlying the 6 deleterious effects of GRK2 up-regulation and the beneficial effects of its inhibition in the heart are not fully understood. Therefore, 7 we have explored the interconnections among a systemic IR status, GRK2 dosage and cardiac insulin sensitivity in adult (9 month-old) animals. GRK2+/- mice display enhanced cardiac insulin sensitivity and mild heart hypertrophy with preserved systolic function. Cardiac gene expression is reprogrammed in these animals, with increased expression of genes related to physiological hypertrophy, while the expression of genes related to pathological hypertrophy or to diabetes/obesity co-morbidities is repressed. Notably, we find that cardiac GRK2 levels increase in situations where IR develops, such as in ob/ob mice or after high fat diet feeding. Our data suggest that GRK2 downregulation/inhibition can help maintain cardiac function in the face of co-morbidities such as IR, diabetes or obesity by sustaining insulin sensitivity and promoting a gene expression reprogramming that confers cardioprotection.Grants from Ministerio de Educación y Ciencia (SAF2011-23800), Fundación para la Investigación Médica Aplicada (FIMA) and UTE project CIMA, The Cardiovascular Network of Ministerio Sanidad y Consumo-Instituto Carlos III (RD06-0014/0037 and RD12/0042/0012), Comunidad de Madrid (S2010/BMD-2332) and EFSD-Novo Nordisk to F.M and UAM Grupo Santander to C.M and Wood-Whelan Research Fellowship from IUBMB to E.L. We also acknowledge institutional support from Fundación Ramón Arece

β1-Blockade Prevents Post-Ischemic Myocardial Decompensation Via β3AR-Dependent Protective Sphingosine-1 Phosphate Signaling

BACKGROUND: Although β-blockers increase survival in patients with heart failure (HF), the mechanisms behind this protection are not fully understood, and not all patients with HF respond favorably to them. We recently showed that, in cardiomyocytes, a reciprocal down-regulation occurs between β1-adrenergic receptors (ARs) and the cardioprotective sphingosine-1-phosphate (S1P) receptor-1 (S1PR1). OBJECTIVES: The authors hypothesized that, in addition to salutary actions due to direct β1AR-blockade, agents such as metoprolol (Meto) may improve post-myocardial infarction (MI) structural and functional outcomes via restored S1PR1 signaling, and sought to determine mechanisms accounting for this effect. METHODS: We tested the in vitro effects of Meto in HEK293 cells and in ventricular cardiomyocytes isolated from neonatal rats. In vivo, we assessed the effects of Meto in MI wild-type and β3AR knockout mice. RESULTS: Here we report that, in vitro, Meto prevents catecholamine-induced down-regulation of S1PR1, a major cardiac protective signaling pathway. In vivo, we show that Meto arrests post-MI HF progression in mice as much as chronic S1P treatment. Importantly, human HF subjects receiving β1AR-blockers display elevated circulating S1P levels, confirming that Meto promotes S1P secretion/signaling. Mechanistically, we found that Meto-induced S1P secretion is β3AR-dependent because Meto infusion in β3AR knockout mice does not elevate circulating S1P levels, nor does it ameliorate post-MI dysfunction, as in wild-type mice. CONCLUSIONS: Our study uncovers a previously unrecognized mechanism by which β1-blockers prevent HF progression in patients with ischemia, suggesting that β3AR dysfunction may account for limited/null efficacy in β1AR-blocker-insensitive HF subjects