Limits...
MicroRNAs as a therapeutic target for cardiovascular diseases.

Mishra PK, Tyagi N, Kumar M, Tyagi SC - J. Cell. Mol. Med. (2009)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology & Biophysics, University of Louisville School of Medicine, KY, USA.

ABSTRACT
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.

Show MeSH

Related in: MedlinePlus

Biogenesis of miRNA and its regulatory mechanisms: miRNAs are encoded from either intergenic regions or introns and sometimes more than one encoded miRNA shares the same transcript (polycistronic). The primary miRNA (pri-miRNA), an approximately 200 kilobases long, capped and polyadenylated transcript, is transcribed by RNA polymerase III (or II) from any of the above mentioned encoding regions of miRNA. The pri-miRNA from intergenic and intronic regions is shown in the upper panel and from polycistronic region is shown in the lower panel of pri-miRNA. Drosha (an RNase III enzyme) along with Pasha (a double strand RNA binding protein) processes pri-miRNA into approximately 70 nucleotide pre-miRNA by cleaving the 5′ cap and polyadenylated tail. The pre-miRNA is transported from the nucleus to the cytoplasm by RAN-GTP exportin 5. Dicer (another RNase III endonuclease) cleaves pre-miRNA into double stranded transient duplex miRNA (22 nucleotides). The double stranded miRNA dissociates into single strands, and only one strand is retained as mature miRNA and it binds to RNA induced silencing complex (RISC). The miRNA-RISC complex regulates the dose of a particular protein by either degrading the complimentary mRNA by using RNAi mechanism or by inhibiting the translational machinery of protein.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3822884&req=5

fig01: Biogenesis of miRNA and its regulatory mechanisms: miRNAs are encoded from either intergenic regions or introns and sometimes more than one encoded miRNA shares the same transcript (polycistronic). The primary miRNA (pri-miRNA), an approximately 200 kilobases long, capped and polyadenylated transcript, is transcribed by RNA polymerase III (or II) from any of the above mentioned encoding regions of miRNA. The pri-miRNA from intergenic and intronic regions is shown in the upper panel and from polycistronic region is shown in the lower panel of pri-miRNA. Drosha (an RNase III enzyme) along with Pasha (a double strand RNA binding protein) processes pri-miRNA into approximately 70 nucleotide pre-miRNA by cleaving the 5′ cap and polyadenylated tail. The pre-miRNA is transported from the nucleus to the cytoplasm by RAN-GTP exportin 5. Dicer (another RNase III endonuclease) cleaves pre-miRNA into double stranded transient duplex miRNA (22 nucleotides). The double stranded miRNA dissociates into single strands, and only one strand is retained as mature miRNA and it binds to RNA induced silencing complex (RISC). The miRNA-RISC complex regulates the dose of a particular protein by either degrading the complimentary mRNA by using RNAi mechanism or by inhibiting the translational machinery of protein.

Mentions: MiRNAs can be derived from individual miRNA genes, introns of protein coding genes or polycistronic transcripts [20]. They are transcribed by RNA polymerase II or III into primary miRNA (pri-miRNA), which are several kilobases long, capped (MGpppG) and polyadenylated [23] (Fig. 1). The pri-miRNAs are processed in nucleus by RNase III enzyme Drosha and the dsRNA binding protein Pasha (also known as DGCR8), into a hairpin-shaped structure of 70–100 nucleotides called preliminary-miRNA (pre-miRNA). Some intronic miRNA precursors, however, bypass Drosha processing to produce miRNA by Dicer, possibly representing an alternative pathway for miRNA biogenesis [24]. The pre-miRNAs are transported from the nucleus to the cytoplasm by RAN-GTP-dependant nuclear export factor, exportin 5 [25, 26] where they are processed by another RNase III enzyme, Dicer. Dicer processes pre-miRNA into a transient ∼18–24 nucleotide duplex. Out of two strands, one strand of miRNA duplex is preferentially retained in the complex that finally becomes the mature miRNA whereas the other strand, also called passenger strand or miRNA*, is degraded and eliminated from the complex [26]. The mature single stranded miRNA is loaded into the miRNA associated multi-protein RNA induced silencing complex (miRNA-RISC) that includes the Argonoute (Ago) proteins [26]. If the 3′ UTR of target sequence precisely matches the miRNA, Ago-2 will bind to the RISC complex, but if there are mismatches, Ago-1 will bind to the RISC [27].


MicroRNAs as a therapeutic target for cardiovascular diseases.

Mishra PK, Tyagi N, Kumar M, Tyagi SC - J. Cell. Mol. Med. (2009)

Biogenesis of miRNA and its regulatory mechanisms: miRNAs are encoded from either intergenic regions or introns and sometimes more than one encoded miRNA shares the same transcript (polycistronic). The primary miRNA (pri-miRNA), an approximately 200 kilobases long, capped and polyadenylated transcript, is transcribed by RNA polymerase III (or II) from any of the above mentioned encoding regions of miRNA. The pri-miRNA from intergenic and intronic regions is shown in the upper panel and from polycistronic region is shown in the lower panel of pri-miRNA. Drosha (an RNase III enzyme) along with Pasha (a double strand RNA binding protein) processes pri-miRNA into approximately 70 nucleotide pre-miRNA by cleaving the 5′ cap and polyadenylated tail. The pre-miRNA is transported from the nucleus to the cytoplasm by RAN-GTP exportin 5. Dicer (another RNase III endonuclease) cleaves pre-miRNA into double stranded transient duplex miRNA (22 nucleotides). The double stranded miRNA dissociates into single strands, and only one strand is retained as mature miRNA and it binds to RNA induced silencing complex (RISC). The miRNA-RISC complex regulates the dose of a particular protein by either degrading the complimentary mRNA by using RNAi mechanism or by inhibiting the translational machinery of protein.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3822884&req=5

fig01: Biogenesis of miRNA and its regulatory mechanisms: miRNAs are encoded from either intergenic regions or introns and sometimes more than one encoded miRNA shares the same transcript (polycistronic). The primary miRNA (pri-miRNA), an approximately 200 kilobases long, capped and polyadenylated transcript, is transcribed by RNA polymerase III (or II) from any of the above mentioned encoding regions of miRNA. The pri-miRNA from intergenic and intronic regions is shown in the upper panel and from polycistronic region is shown in the lower panel of pri-miRNA. Drosha (an RNase III enzyme) along with Pasha (a double strand RNA binding protein) processes pri-miRNA into approximately 70 nucleotide pre-miRNA by cleaving the 5′ cap and polyadenylated tail. The pre-miRNA is transported from the nucleus to the cytoplasm by RAN-GTP exportin 5. Dicer (another RNase III endonuclease) cleaves pre-miRNA into double stranded transient duplex miRNA (22 nucleotides). The double stranded miRNA dissociates into single strands, and only one strand is retained as mature miRNA and it binds to RNA induced silencing complex (RISC). The miRNA-RISC complex regulates the dose of a particular protein by either degrading the complimentary mRNA by using RNAi mechanism or by inhibiting the translational machinery of protein.
Mentions: MiRNAs can be derived from individual miRNA genes, introns of protein coding genes or polycistronic transcripts [20]. They are transcribed by RNA polymerase II or III into primary miRNA (pri-miRNA), which are several kilobases long, capped (MGpppG) and polyadenylated [23] (Fig. 1). The pri-miRNAs are processed in nucleus by RNase III enzyme Drosha and the dsRNA binding protein Pasha (also known as DGCR8), into a hairpin-shaped structure of 70–100 nucleotides called preliminary-miRNA (pre-miRNA). Some intronic miRNA precursors, however, bypass Drosha processing to produce miRNA by Dicer, possibly representing an alternative pathway for miRNA biogenesis [24]. The pre-miRNAs are transported from the nucleus to the cytoplasm by RAN-GTP-dependant nuclear export factor, exportin 5 [25, 26] where they are processed by another RNase III enzyme, Dicer. Dicer processes pre-miRNA into a transient ∼18–24 nucleotide duplex. Out of two strands, one strand of miRNA duplex is preferentially retained in the complex that finally becomes the mature miRNA whereas the other strand, also called passenger strand or miRNA*, is degraded and eliminated from the complex [26]. The mature single stranded miRNA is loaded into the miRNA associated multi-protein RNA induced silencing complex (miRNA-RISC) that includes the Argonoute (Ago) proteins [26]. If the 3′ UTR of target sequence precisely matches the miRNA, Ago-2 will bind to the RISC complex, but if there are mismatches, Ago-1 will bind to the RISC [27].

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology & Biophysics, University of Louisville School of Medicine, KY, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus