Abstract
Large artery stiffness is a major risk factor underlying cardiovascular disease. However, the molecular mechanisms driving this pathological process are poorly understood. Previous studies indicate that the age-associated decline of miR-181b levels can accelerate aortic stiffening by activating TGF-β (transforming growth factor β) signaling. Here, we studied the physiological role of miR-181b in mediating arginine vasopressin (AVP)-induced stiffening of vascular smooth muscle cells (VSMCs) isolated from aorta. We found that AVP treatment increases VSMC stiffness and causes marked reductions in both pre-miR-181b and miR-181b expression. Transfecting VSMCs with a miR-181b mimic abolishes AVP-induced stiffening, indicating that this stiffening response is dependent on AVP's ability to reduce miR-181b levels. In addition, deletion of translin or inactivation of the TN/TX (translin/trax) RNAse prevents the AVP-induced decrease in pre-miR-181b/miR-181b levels and VSMC stiffening, indicating that these effects are mediated by this microRNA-degrading enzyme. Interestingly, AVP exposure increases extracellular TGF-β levels in a TN/TX-dependent manner and pretreatment of VSMCs with TGF-β neutralizing antibodies inhibits AVP-induced stiffness. Lastly, we have ascertained that age-associated aortic stiffening in vivo is prevented in mice homozygous for the TX (E126A) point mutation, which abolishes TN/TX RNase activity. Taken together, these findings provide compelling evidence that TN/TX RNase activity plays a critical role in regulating VSMC stiffness via degradation of pre-miR-181b and TGF-β pathway activation. Our findings also indicate that therapeutic strategies capable of blocking TN/TX-mediated reductions in miR-181b levels may confer protection against large artery stiffness and associated cardiovascular diseases.
Original language | English (US) |
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Pages (from-to) | 831-839 |
Number of pages | 9 |
Journal | Hypertension |
Volume | 78 |
Issue number | 3 |
DOIs | |
State | Published - Sep 1 2021 |
Keywords
- aorta
- cardiovascular diseases
- microRNA degradation
- risk factors
- vascular smooth muscle
- vasopressin
ASJC Scopus subject areas
- Internal Medicine