Degradation of Premature-miR-181b by the Translin/Trax RNase Increases Vascular Smooth Muscle Cell Stiffness

Eric Tuday, Mitsunori Nakano, Kei Akiyoshi, Xiuping Fu, Aparna P. Shah, Atsushi Yamaguchi, Charles Steenbergen, Lakshmi Santhanam, Steven S. An, Dan Berkowitz, Jay M. Baraban, Samarjit Das

Research output: Contribution to journalArticlepeer-review


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 languageEnglish (US)
Pages (from-to)831-839
Number of pages9
Issue number3
StatePublished - Sep 1 2021


  • aorta
  • cardiovascular diseases
  • microRNA degradation
  • risk factors
  • vascular smooth muscle
  • vasopressin

ASJC Scopus subject areas

  • Internal Medicine


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