Deciphering Non-coding RNAs in Cardiovascular Health and Disease

After being long considered as “junk” in the human genome, non-coding RNAs (ncRNAs) currently represent one of the newest frontiers in cardiovascular disease (CVD) since they have emerged in recent years as potential therapeutic targets. Different types of ncRNAs exist, including small ncRNAs that have fewer than 200 nucleotides, which are mostly known as microRNAs (miRNAs), and long ncRNAs that have more than 200 nucleotides. Recent discoveries on the role of ncRNAs in epigenetic and transcriptional regulation, atherosclerosis, myocardial ischemia/reperfusion (I/R) injury and infarction (MI), adverse cardiac remodeling and hypertrophy, insulin resistance, and diabetic cardiomyopathy prompted vast interest in exploring candidate ncRNAs for utilization as potential therapeutic targets and/or diagnostic/prognostic biomarkers in CVDs. This review will discuss our current knowledge concerning the roles of different types of ncRNAs in cardiovascular health and disease and provide some insight on the cardioprotective signaling pathways elicited by the non-coding genome. We will highlight important basic and clinical breakthroughs that support employing ncRNAs for treatment or early diagnosis of a variety of CVDs, and also depict the most relevant limitations that challenge this novel therapeutic approach

Reperfusion Therapy with Rapamycin Attenuates Myocardial Infarction through Activation of AKT and ERK

Prompt coronary reperfusion is the gold standard for minimizing injury following acute myocardial infarction. Rapamycin, mammalian target of Rapamycin (mTOR) inhibitor, exerts preconditioning-like cardioprotective effects against ischemia/reperfusion (I/R) injury. We hypothesized that Rapamycin, given at the onset of reperfusion, reduces myocardial infarct size through modulation of mTOR complexes. Adult C57 male mice were subjected to 30 min of myocardial ischemia followed by reperfusion for 1 hour/24 hours. Rapamycin (0.25 mg/kg) or DMSO (7.5%) was injected intracardially at the onset of reperfusion. Post-I/R survival (87%) and cardiac function (fractional shortening, FS: 28.63±3.01%) were improved in Rapamycin-treated mice compared to DMSO (survival: 63%, FS: 17.4±2.6%). Rapamycin caused significant reduction in myocardial infarct size (IS: 26.2±2.2%) and apoptosis (2.87±0.64%) as compared to DMSO-treated mice (IS: 47.0±2.3%; apoptosis: 7.39±0.81%). Rapamycin induced phosphorylation of AKT S473 (target of mTORC2) but abolished ribosomal protein S6 phosphorylation (target of mTORC1) after I/R. Rapamycin induced phosphorylation of ERK1/2 but inhibited p38 phosphorylation. Infarct-limiting effect of Rapamycin was abolished with ERK inhibitor, PD98059. Rapamycin also attenuated Bax and increased Bcl-2/Bax ratio. These results suggest that reperfusion therapy with Rapamycin protects the heart against I/R injury by selective activation of mTORC2 and ERK with concurrent inhibition of mTORC1 and p38

Characterization of a murine model of monocrotaline pyrrole-induced acute lung injury

<p>Abstract</p> <p>Background</p> <p>New animal models of chronic pulmonary hypertension in mice are needed. The injection of monocrotaline is an established model of pulmonary hypertension in rats. The aim of this study was to establish a murine model of pulmonary hypertension by injection of the active metabolite, monocrotaline pyrrole.</p> <p>Methods</p> <p>Survival studies, computed tomographic scanning, histology, bronchoalveolar lavage were performed, and arterial blood gases and hemodynamics were measured in animals which received an intravenous injection of different doses of monocrotaline pyrrole.</p> <p>Results</p> <p>Monocrotaline pyrrole induced pulmonary hypertension in Sprague Dawley rats. When injected into mice, monocrotaline pyrrole induced dose-dependant mortality in C57Bl6/N and BALB/c mice (dose range 6–15 mg/kg bodyweight). At a dose of 10 mg/kg bodyweight, mice developed a typical early-phase acute lung injury, characterized by lung edema, neutrophil influx, hypoxemia and reduced lung compliance. In the late phase, monocrotaline pyrrole injection resulted in limited lung fibrosis and no obvious pulmonary hypertension.</p> <p>Conclusion</p> <p>Monocrotaline and monocrotaline pyrrole pneumotoxicity substantially differs between the animal species.</p