The tumor suppressor p53, encoded by the TP53 gene, is recognized as the guardian of the human genome because it regulates many downstream genes to exercise its function in cell cycle and cell death. Recent reports have revealed that several microRNAs (miRNAs) are important components of the p53 tumor suppressor network with miR-125b and miR-504 directly targeting TP53. In this report, we use a screening method to identify that two miRNAs (miR-25 and miR-30d) directly target the 3'UTR of TP53 to down-regulate p53 protein levels and reduce the expression of genes that are transcriptionally activated by p53. Correspondingly, both miR-25 and miR-30d adversely affect apoptotic cell death, cell cycle arrest, and cellular senescence. Inhibition of either miR-25 or miR-30d expression increases endogenous p53 expression and elevates cellular apoptosis in several cell lines, including one from multiple myeloma that has little TP53 mutations. Thus, beyond miR-125b and miR-504, the human TP53 gene is negatively regulated by two more miRNAs: miR-25 and miR-30d.

MicroRNA 21 (miR-21) is overexpressed in virtually all types of carcinomas and various types of hematological malignancies. To determine whether miR-21 promotes tumor development in vivo, we knocked out the miR-21 allele in mice. In response to the 7,12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate mouse skin carcinogenesis protocol, miR-21-null mice showed a significant reduction in papilloma formation compared with wild-type mice. We revealed that cellular apoptosis was elevated and cell proliferation was decreased in mice deficient of miR-21 compared to wild-type animals. In addition, we found that a large number of validated or predicted miR-21 target genes were up-regulated in miR-21-null keratinocytes, which are precursor cells to skin papillomas. Specifically, up-regulation of Spry1, Pten, and Pdcd4 when miR-21 was ablated coincided with reduced phosphorylation of ERK, AKT, and JNK, three major downstream effectors of Ras activation that plays a predominant role in DMBA-initiated skin carcinogenesis. These results provide in vivo evidence that miR-21 exerts its oncogenic function through negatively regulating its target genes.

MicroRNAs (miRNAs) are tiny, endogenous, conserved, non-coding RNAs that negatively modulate gene expression by either promoting the degradation of mRNA or down-regulating the protein production by translational repression. They maintain optimal dose of cellular proteins and thus play a crucial role in the regulation of biological functions. Recent discovery of miRNAs in the heart and their differential expressions in pathological conditions provide glimpses of undiscovered regulatory mechanisms underlying cardiovascular diseases. Nearly 50 miRNAs are overexpressed in mouse heart. The implication of several miRNAs in cardiovascular diseases has been well documented such as miRNA-1 in arrhythmia, miRNA-29 in cardiac fibrosis, miRNA-126 in angiogenesis and miRNA-133 in cardiac hypertrophy. Aberrant expression of Dicer (an enzyme required for maturation of all miRNAs) during heart failure indicates its direct involvement in the regulation of cardiac diseases. MiRNAs and Dicer provide a particular layer of network of precise gene regulation in heart and vascular tissues in a spatiotemporal manner suggesting their implications as a powerful intervention tool for therapy. The combined strategy of manipulating miRNAs in stem cells for their target directed differentiation and optimizing the mode of delivery of miRNAs to the desired cells would determine the future potential of miRNAs to treat a disease. This review embodies the recent progress made in microRNomics of cardiovascular diseases and the future of miRNAs as a potential therapeutic target - the putative challenges and the approaches to deal with it.

Homocysteine (Hcy) causes cerebrovascular dysfunction by inducing oxidative stress. However, to date, there are no strategies to prevent Hcy-induced oxidative damage. Hcy is an H 2 S precursor formed from methionine (Met) metabolism. We aimed to investigate whether H 2 S ameliorated Met-induced oxidative stress in mouse brain endothelial cells (bEnd3). The bEnd3 cells were exposed to Met treatment in the presence or absence of NaHS (donor of H 2 S). Met-induced cell toxicity increased the levels of free radicals in a concentration-dependent manner. Met increased NADPH-oxidase-4 (NOX-4) expression and mitigated thioredxion-1(Trx-1) expression. Pretreatment of bEnd3 with NaHS (0.05 mM) attenuated the production of free radicals in the presence of Met and protected the cells from oxidative damage. Furthermore, NaHS enhanced inhibitory effects of apocynin, N-acetyl-l-cysteine (NAC), reduced glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), N -nitro-l-arginine methyl ester (L-NAME) on ROS production and redox enzymes levels induced by Met. In conclusion, the administration of H 2 S protected the cells from oxidative stress induced by hyperhomocysteinemia (HHcy), which suggested that NaHS/H 2 S may have therapeutic potential against Met-induced oxidative stress. Antioxid. Redox Signal. 11,[25][26][27][28][29][30][31][32][33]