Recent studies have begun to reveal critical roles of microRNAs (miRNAs) in the pathogenesis of cardiac hypertrophy and dysfunction. In this study, we tested whether a transforming growth factor-β (TGF-β)-regulated miRNA played a pivotal role in the development of cardiac hypertrophy and heart failure (HF). We observed that miR-27b was upregulated in hearts of cardiomyocyte-specific Smad4 knockout mice, which developed cardiac hypertrophy. In vitro experiments showed that the miR-27b expression could be inhibited by TGF-β1 and that its overexpression promoted hypertrophic cell growth, while the miR-27b suppression led to inhibition of the hypertrophic cell growth caused by phenylephrine (PE) treatment. Furthermore, the analysis of transgenic mice with cardiomyocyte-specific overexpression of miR-27b revealed that miR-27b overexpression was sufficient to induce cardiac hypertrophy and dysfunction. We validated the peroxisome proliferator-activated receptor-γ (PPAR-γ) as a direct target of miR-27b in cardiomyocyte. Consistently, the miR-27b transgenic mice displayed significantly lower levels of PPAR-γ than the control mice. Furthermore, in vivo silencing of miR-27b using a specific antagomir in a pressure-overload-induced mouse model of HF increased cardiac PPAR-γ expression, attenuated cardiac hypertrophy and dysfunction. The results of our study demonstrate that TGF-β1-regulated miR-27b is involved in the regulation of cardiac hypertrophy, and validate miR-27b as an efficient therapeutic target for cardiac diseases.
Progranulin (PGRN), an autocrine growth factor, has multiple physiological functions and is widely involved in the pathogenesis of many types of diseases. The pivotal anti-inflammatory function of PGRN in rheumatoid arthritis encouraged us to examine the role of PGRN in acute kidney injury (AKI). We found that levels of PGRN were significantly reduced in the kidney in a mouse model of renal ischemia/reperfusion injury. We also observed that PGRN deficiency (Grn(-/-) mice) significantly aggravated renal injury as evidenced by higher serum creatinine, more severe morphological injury, increased tubular epithelial cell death, and tubulointerstitial neutrophil and macrophage infiltration versus wild-type mice. In vitro, we found that recombinant human PGRN attenuated hypoxia-induced inflammatory actions and apoptosis in proximal tubule epithelial cells, at least in part associated with a nucleotide-binding oligomerization domain containing 2 (NOD2)-mediated immune response. Importantly, pretreatment with or delayed administration of recombinant human PGRN protected against or promoted recovery from renal ischemia/reperfusion injury in wild-type and Grn(-/-) mice. Similar protective effects were also found in cisplatin-induced AKI. Thus, our findings provide a better understanding of the biological activities of PGRN in the kidney and suggest that PGRN may be an innovative therapeutic strategy for treating patients with AKI.
Lung cancer (LC) is a leading cause of cancer‐related death in the Western world. Patients with LC usually have poor prognosis due to the difficulties in detecting tumors at early stages. Multiple studies have shown that circulating miRNAs might be promising biomarkers for early detection of LC. We aimed to provide an overview of published studies on circulating miRNA markers for early detection of LC and to summarize their diagnostic performance in Western populations. A systematic literature search was performed in PubMed and ISI Web of Knowledge to find relevant studies published up to 11 August 2017. Information on study design, population characteristics, miRNA markers, and diagnostic accuracy (including sensitivity, specificity, and AUC) were independently extracted by two reviewers. Overall, 17 studies evaluating 35 circulating miRNA markers and 19 miRNA panels in serum or plasma were included. The median sensitivity (range) and specificity (range) were, respectively, 78.4% (51.7%‐100%) and 78.7% (42.9%‐93.5%) for individual miRNAs, and 83.0% (64.0%‐100%) and 84.9% (71.0%‐100%) for miRNA panels. Most studies incorporated individual miRNA markers as panels (with 2‐34 markers), with multiple miRNA‐based panels generally outperforming individual markers. Two promising miRNA panels were discovered and verified in prospective cohorts. Of note, both studies exclusively applied miRNA ratios when building up panels. In conclusion, circulating miRNAs may bear potential for noninvasive LC screening, but large studies conducted in screening or longitudinal settings are needed to validate the promising results and optimize the marker panels.
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