Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cardiovascular disease remains the leading cause of mortality in westernized countries, despite optimum medical therapy to reduce the levels of low-density lipoprotein (LDL)-associated cholesterol. The pursuit of novel therapies to target the residual risk has focused on raising the levels of high-density lipoprotein (HDL)-associated cholesterol in order to exploit its atheroprotective effects. MicroRNAs (miRNAs) have emerged as important post-transcriptional regulators of lipid metabolism and are thus a new class of target for therapeutic intervention. MicroRNA-33a and microRNA-33b (miR-33a/b) are intronic miRNAs whose encoding regions are embedded in the sterol-response-element-binding protein genes SREBF2 and SREBF1 (refs 3-5), respectively. These miRNAs repress expression of the cholesterol transporter ABCA1, which is a key regulator of HDL biogenesis. Recent studies in mice suggest that antagonizing miR-33a may be an effective strategy for raising plasma HDL levels and providing protection against atherosclerosis; however, extrapolating these findings to humans is complicated by the fact that mice lack miR-33b, which is present only in the SREBF1 gene of medium and large mammals. Here we show in African green monkeys that systemic delivery of an anti-miRNA oligonucleotide that targets both miR-33a and miR-33b increased hepatic expression of ABCA1 and induced a sustained increase in plasma HDL levels over 12 weeks. Notably, miR-33 antagonism in this non-human primate model also increased the expression of miR-33 target genes involved in fatty acid oxidation (CROT, CPT1A, HADHB and PRKAA1) and reduced the expression of genes involved in fatty acid synthesis (SREBF1, FASN, ACLY and ACACA), resulting in a marked suppression of the plasma levels of very-low-density lipoprotein (VLDL)-associated triglycerides, a finding that has not previously been observed in mice. These data establish, in a model that is highly relevant to humans, that pharmacological inhibition of miR-33a and miR-33b is a promising therapeutic strategy to raise plasma HDL and lower VLDL triglyceride levels for the treatment of dyslipidaemias that increase cardiovascular disease risk.
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PMID:Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides. 2209 69

MicroRNAs have emerged as important post-transcriptional regulators of lipid metabolism, and represent a new class of targets for therapeutic intervention. Recently, microRNA-33a and b (miR-33a/b) were discovered as key regulators of metabolic programs including cholesterol and fatty acid homeostasis. These intronic microRNAs are embedded in the sterol response element binding protein genes, SREBF2 and SREBF1, which code for transcription factors that coordinate cholesterol and fatty acid synthesis. By repressing a variety of genes involved in cholesterol export and fatty acid oxidation, including ABCA1, CROT, CPT1, HADHB and PRKAA1, miR-33a/b act in concert with their host genes to boost cellular sterol levels. Recent work in animal models has shown that inhibition of these small non-coding RNAs has potent effects on lipoprotein metabolism, including increasing plasma high-density lipoprotein (HDL) and reducing very low density lipoprotein (VLDL) triglycerides. Furthermore, other microRNAs are being discovered that also target the ABCA1 pathway, including miR-758, suggesting that miRNAs may work cooperatively to regulate this pathway. These exciting findings support the development of microRNA antagonists as potential therapeutics for the treatment of dyslipidaemia, atherosclerosis and related metabolic diseases.
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PMID:MicroRNAs regulating lipid metabolism in atherogenesis. 2227 26