Abstract
The blood levels of microRNA-122 (miR-122) is associated with the severity of cardiovascular disorders, and targeting it with efficient and safer miR inhibitors could be a promising approach. Here, we report the generation of a γ-peptide nucleic acid (γPNA)-based miR-122 inhibitor (γP-122-I) that rescues vascular endothelial dysfunction in mice fed a high-fat diet. We synthesized diethylene glycol-containing γP-122-I and found that its systemic administration counteracted high-fat diet (HFD)-feeding-associated increase in blood and aortic miR-122 levels, impaired endothelial function, and reduced glycemic control. A comprehensive safety analysis established that γP-122-I affects neither the complete blood count nor biochemical tests of liver and kidney functions during acute exposure. In addition, long-term exposure to γP-122-I did not change the overall adiposity, or histology of the kidney, liver, and heart. Thus, γP-122-I rescues endothelial dysfunction without any evidence of toxicity in vivo and demonstrates the suitability of γPNA technology in generating efficient and safer miR inhibitors.
Highlights
Hypertension is a common impediment in patients with type 2 diabetes, and both diabetes and hypertension are individually associated with increased risk of cardiovascular events.[1]
We synthesized diethylene glycol-containing γ-peptide nucleic acid (γPNA)-based miR-122 inhibitors (Figure 1A,B, γP-122-I) and scrambled controls (Figure 1B, γP-SC). γPNAs were synthesized using established solid-phase protocols,[59] and their quality was determined by highperformance liquid chromatography (HPLC) and matrixassisted laser desorption/ionization (MALDI) spectrometry (Figure S1)
We evaluated the denaturation of heteroduplexes formed from a commercially available miR-122 inhibitor (C-122-I) and the same target construct
Summary
Hypertension is a common impediment in patients with type 2 diabetes, and both diabetes and hypertension are individually associated with increased risk of cardiovascular events.[1] Patients with diabetes are at higher risk of nondipping hypertension[2−4] and heart/kidney failure.[5−12] Current treatment approaches fail to decrease unwanted cardiovascular outcomes in these patients.[13,14] In patients with diabetes, the risk of hypertension is preceded and predicted by endothelial dysfunction.[15] One promising approach to effectively combat endothelial dysfunction involves targeting microRNAs (miRs).[16] miR-122-5p (miR-122) is considered a target because of its increased levels in patients with diabetes and/or obesity,[17−23] which correlates with severity of cardiovascular disorders.[24−27] miR-122 is primarily expressed in the liver and released into the blood.[28−30] Its release into the blood is increased in the contexts of obesity, non alcoholic fatty liver disease, and liver toxicity.[31,32] We recently demonstrated that in endothelial cells, miR-122 regulates expression of the proinflammatory miR-204, a molecule that promotes vascular endothelial dysfunction.[33] a recent report established that the inhibition of miR-122 prevents atherosclerosis in ApoE‐/‐ mice, which are hypercholesterolemic and spontaneously develop atherosclerosis.[34] we postulate that the systemic inhibition of miR-122 will prevent the development of endothelial dysfunction
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