Time Dependent Distribution of MicroRNA 144 after Intravenous Delivery
1Heart Institute, UC Department of Pediatrics3333 Burnet Avenue Cincinnati Ohio 45229-3026, USA.
Background:
miR-144 has potential benefits in protecting against myocardial ischemia and suppression of tumor growth. We have previously shown that a single intravenous injection of miR-144 provides potent cardioprotection, but its kinetics and distribution are not known.
Methods:
Single stranded mature miR-144 or Cy3-labelled-miR-144 was delivered into C57/B6 mice by tail vein injection.
Results:
After intravenous injection, the signal of Cy3-labelled-miR-144 in the kidney, brain, heart and liver peaks at 60 minutes, and is predominantly localised to the endothelium at that stage. In the kidney and heart, Cy3-labelled-miR-144 signal is detectable within the parenchymal tissues for at least 3 days, after which it starts to decrease, but brain Cy3-miR-144 signal rapidly decreases after 1 hour, and is lost at day 1, with no parenchymal uptake detected. Cy3-miR-144 signal can be detected until day 28 in the liver. Stem loop RTPCR confirmed the temporal pattern shown by miR-144 in kidney, brain and heart, but in liver there was a continuous rise following the initial injection until day 28 with no signs of decrease, suggesting de-novo synthesis.
Conclusion:
There is early endothelial uptake of injected miR-144 followed by organ-specific distribution and kinetics. In the liver, there appears to be a positive feedback process that leads to continued accumulation of miR-144 that persists for at least 28 days. These observations should be taken into account when designing experiments utilizing parenteral miR-144 and assessing the biology of its actions.
Insights
MicroRNA-144 (miR-144) shows organ-specific distribution after intravenous injection in mice. Liver exhibits sustained miR-144 accumulation for at least 28 days, suggesting de novo synthesis.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- MicroRNA-144 (miR-144) demonstrates potential in treating myocardial ischemia and suppressing tumor growth.
- Previous studies confirmed potent cardioprotection from a single intravenous injection of miR-144.
- The pharmacokinetic and biodistribution profiles of systemically administered miR-144 were previously unknown.
Purpose of the Study:
- To investigate the kinetics and distribution of microRNA-144 (miR-144) following intravenous administration in mice.
- To understand the organ-specific biodistribution and persistence of miR-144.
- To inform experimental design and biological assessment of parenteral miR-144.
Main Methods:
- Single-stranded mature miR-144, including a Cy3-labeled version, was administered to C57/B6 mice via tail vein injection.
- The distribution and signal intensity of Cy3-labeled miR-144 were monitored in various organs (kidney, brain, heart, liver) over time.
- Stem loop RT-PCR was employed to confirm the temporal expression patterns of miR-144 in key tissues.
Main Results:
- Cy3-labeled miR-144 exhibited peak signal in the kidney, brain, heart, and liver at 60 minutes post-injection, primarily localized to the endothelium.
- miR-144 signal persisted in kidney and heart parenchymal tissues for at least 3 days, while brain signal rapidly diminished.
- Sustained miR-144 signal was detected in the liver up to 28 days, with continuous rise suggesting de novo synthesis, unlike other organs.
Conclusions:
- Injected miR-144 undergoes early endothelial uptake followed by organ-specific distribution and varying kinetics.
- The liver demonstrates a unique positive feedback mechanism leading to sustained miR-144 accumulation for at least 28 days.
- These biodistribution findings are crucial for designing future experiments involving parenteral miR-144 and interpreting its biological effects.
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