Silencing of microRNA-106b-5p prevents doxorubicin-mediated cardiotoxicity through modulation of the PR55α/YY1/sST2 signaling axis.

Clinical use of doxorubicin (Dox), an anthracycline with potent anti-tumor effects, is limited because of its highly chemotherapy-induced cardiotoxicity (CIC). After myocardial infarction (MI), we have recently identified Yin Yang-1 (YY1) and histone deacetylase 4 (HDAC4) as two factors involved in the overexpression of the isoform soluble suppression of tumorigenicity 2 (sST2) protein, which acts as a decoy receptor blocking the favorable effects of IL-33. Therefore, high levels of sST2 are associated with increased fibrosis, remodeling, and worse cardiovascular outcomes. No data exist on the role of the YY1/HDAC4/sST2 axis in CIC. This study aimed to evaluate the pathophysiological implication of the molecular YY1/HDAC4/sST2 axis in remodeling that is developed in patients treated with Dox as well as to suggest a novel molecular therapy to prevent anthracycline-induced cardiotoxicity. Here, we have characterized a novel nexus between miR106b-5p (miR-106b) levels and the YY1/HDAC4 axis in relation to the cardiac expression of sST2 using two experimental models with Dox-induced cardiotoxicity. The addition of Dox (5 µM) to human induced pluripotent stem cell-derived cardiomyocytes induced cellular apoptotic death via upregulation of miR-106b-5p (miR-106b), which was confirmed by specific mimic sequences. A functional blockage of miR-106b using the locked nucleic acid antagomir inhibited Dox-induced cardiotoxicity.

Empagliflozin improves post-infarction cardiac remodeling through GTP enzyme cyclohydrolase 1 and irrespective of diabetes status.

Sodium-glucose co-transporter-2 inhibitors (SGLT2i) have shown to prevent heart failure progression, although the mechanisms remain poorly understood. Here we evaluated the effect of empagliflozin (EMPA, SGLT2i) in cardiac remodeling after myocardial infarction, the interplay with diabetes status and the role of cardiac GTP enzyme cyclohydrolase 1 (cGCH1). A rat model of diabetes (50 mg/kg streptozotocin, i.p.) was subjected to myocardial infarction and left ventricular systolic dysfunction, by ligation of the left anterior descending coronary artery. EMPA therapy significantly improved cardiac remodeling parameters and ameliorated processes of fibrosis and hypertrophy, in both non-diabetic and diabetic rats. This cardioprotective effect related with a significant increase in myocardial expression levels of cGCH1, which led to activation of nNOS and eNOS, and inhibition of iNOS, and subsequently resulted in increasing of NO levels and decreasing O2.- and nitrotyrosine levels. These effects were replicated in a cardiomyocyte biomechanical stretching diabetic model, where silencing cGCH1 blocked the preventive effect of EMPA. The beneficial effects were observed irrespective of diabetes status, although the magnitude was greater in presence of diabetes. Empagliflozin improves myocardial remodeling after myocardial infarction through overexpression of cGCH1, and irrespective of diabetes status.

Pharmacological inhibition of the mitochondrial NADPH oxidase 4/PKCα/Gal-3 pathway reduces left ventricular fibrosis following myocardial infarction.

Although the initial reparative fibrosis after myocardial infarction (MI) is crucial for preventing rupture of the ventricular wall, an exaggerated fibrotic response and reactive fibrosis outside the injured area are detrimental. Although metformin prevents adverse cardiac remodeling, as well as provides glycemic control, the underlying mechanisms remain poorly documented. This study describes the effect of mitochondrial NADPH oxidase 4 (mitoNox) and protein kinase C-alpha (PKCα) on the cardiac fibrosis and galectin 3 (Gal-3) expression. Randomly rats underwent MI, received metformin or saline solution. A model of biomechanical strain and co-culturewas used to enable cross talk between cardiomyocytes and fibroblasts. Long-term metformin treatment after MIwas associated with (1) a reduction in myocardial fibrosis and Gal-3 levels; (2) an increase in adenosine monophosphate-activated protein kinase (AMPK) α1/α2 levels; and (3) an inhibition of both mRNA expression and enzymatic activities of mitoNox and PKCα. These findings were replicated in the cellular model, where the silencing of AMPK expression blocked the ability of metformin to protect cardiomyocytes from strain. The use of specific inhibitors or small interference RNA provided evidence that PKCα is downstream of mitoNox, and that the activation of this pathway results in Gal-3 upregulation.The Gal-3 secreted by cardiomyocytes has a paracrine effect on cardiac fibroblasts, inducing their activation. In conclusion, a metformin-induced increase in AMPK improves myocardial remodeling post-MI, which is related to the inhibition of the mitoNox/PKCα/Gal-3 pathway. Manipulation of this pathway might offer new therapeutic options against adverse cardiac remodeling, in terms of preventing the activation of the present fibroblast population.

Modulation of IL-33/ST2 system in postinfarction heart failure: correlation with cardiac remodelling markers.

BACKGROUND: Interleukin (IL)-33 and sST2 are molecules with an opposite pathophysiologic implications in the myocardial response after acute myocardial infarction (AMI). Both may be a target for therapeutic interventions. The kinetics of IL-33 and sST2 expression in infarcted myocardium and their correlation with the ongoing processes of fibrosis, inflammation and apoptosis remains poorly defined. MATERIALS AND METHODS: Fifty Wistar rats underwent left anterior descending coronary artery surgical ligation and were sacrificed at 1, 2, 4, 12 or 24 weeks post-AMI. A sham-operated group was also included. The mRNA cardiac expression levels of IL-33, sST2, fibrosis markers, inflammatory markers and apoptosis markers were assessed by RT-PCR. The protein expression of IL-33 was also measured by Western blotting. RESULTS: The mRNA levels of IL-33 and sST2 were upregulated in the infarcted myocardium during the first week after AMI. However, while IL-33 levels remained elevated during the first 12 weeks post-AMI, sST2 levels showed a marked drop at 4 weeks. IL-33 protein expression showed a similar kinetic than mRNA expression. The expression of sST2 positively correlated with cardiac gene expression of inflammatory and fibrosis markers. However, the IL-33 level did not correlate with these cardiac remodelling markers. No correlation of sST2 with apoptosis markers was observed. CONCLUSION: After AMI, expression of sST2 is rapidly upregulated during the first 4 weeks and, in contrast to IL-33, its levels correlated with the ongoing processes of fibrosis and inflammation. These findings suggest differential regulation of IL33 and sST2. Therapeutic modulation of early sST2 expression may be of greater importance to prevent adverse remodelling after AMI.