Year-end Sale % OFF 
Abstract
BackgroundEndothelial dysfunction and arterial stiffening play major roles in cardiovascular diseases. The critical role for the miR-181 family in vascular inflammation has been documented. Here we tested whether the miR-181 family can influence the pathogenesis of hypertension and vascular stiffening.Methods and resultsqPCR data showed a significant decrease in miR-181b expression in the aorta of the older mice. Eight miR-181a1/b1-/- mice and wild types (C57BL6J:WT) were followed weekly for pulse wave velocity (PWV) and blood pressure measurements. After 20 weeks, the mice were tested for endothelial function and aortic modulus. There was a progressive increase in PWV and higher systolic blood pressure in miR-181a1/b1-/- mice compared with WTs. At 21 weeks, aortic modulus was significantly greater in the miR-181a1/b1-/- group, and serum TGF-β was found to be elevated at this time. A luciferase reporter assay confirmed miR-181b targets TGF-βi (TGF-β induced) in the aortic VSMCs. In contrast, wire myography revealed unaltered endothelial function along with higher nitric oxide production in the miR-181a1/b1-/- group. Cultured VECs and VSMCs from the mouse aorta showed more secreted TGF-β in VSMCs of the miR-181a1/b1-/- group; whereas, no change was observed from VECs. Circulating levels of angiotensin II were similar in both groups. Treatment with losartan (0.6 g/L) prevented the increase in PWV, blood pressure, and vascular stiffness in miR-181a1/b1-/- mice. Immunohistochemistry and western blot for p-SMAD2/3 validated the inhibitory effect of losartan on TGF-β signaling in miR-181a1/b1-/- mice.ConclusionsDecreased miR-181b with aging plays a critical role in ECM remodeling by removing the brake on the TGF-β, pSMAD2/3 pathway.
Highlights
Hypertension is a major cause of morbidity and mortality worldwide
MiR-181a has been reported to be decreased in vascular smooth muscle cells (VSMCs) when stimulated by angiotensin II, whereas overexpression of miR-181a resulted in inhibition of adhesion of VSMCs to collagen and reduced expression of osteopontin, a multifunctional protein found in abundance in atherosclerotic plaques.[9]
Blood pressure was measured bi-weekly (n = 8), and higher systolic blood pressure in miR181a1/b1-/- mice (n = 8) compared to with losartan. (WT) were observed (20wk WT: 102±2.6mmHg vs. a/b KO: 111±2.1mmHg, p = 0.015). (Fig 2B) On the other hand, there was no significant difference in diastolic blood pressure between the two phenotypes at 20 weeks (WT: 75 ± 2.9 mmHg vs. a/b KO: 80 ± 2.4 mmHg, p = 0.20)
Summary
Hypertension is a major cause of morbidity and mortality worldwide. Increased aortic stiffness is one of the major factors that disproportionately increases central arterial pressure, creates systolic hypertension, and increases pulse pressure.[1,2,3,4] The remodeling of extracellular matrix (ECM) by decreased elastin or it’s fracturing, increased collagen deposition, endothelial dysfunction, and cross-linking of ECM, are the major contributors of increased vascular stiffness.[1, 5]Many miRNAs contribute to vascular dysfunction, but among these, miR-145 and miR181b have been found to be key regulators of vascular inflammation in ApoE signaling pathways.[6, 7] In the ApoE-deficient mouse model, delivering miR-181b was found to protect against vascular inflammation by directly binding at the 3’-UTR of importin-α3, a key regulator of the NF-κB signaling pathway.[7, 8] From human plasma samples, it has been shown that in coronary artery disease, the circulating level of miR-181b expression is significantly lower compared to healthy controls.[7]. Endothelial dysfunction and arterial stiffening play major roles in cardiovascular diseases. The critical role for the miR-181 family in vascular inflammation has been documented. We tested whether the miR-181 family can influence the pathogenesis of hypertension and vascular stiffening
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
