Degradation of Premature-miR-181b by the Translin/Trax RNase Increases Vascular Smooth Muscle Cell Stiffness. Issue 3 (26th July 2021)

• Record Type: Journal Article
• Authors: Tuday, Eric; Nakano, Mitsunori; Akiyoshi, Kei; Fu, Xiuping; Shah, Aparna P.; Yamaguchi, Atsushi; Steenbergen, Charles; Santhanam, Lakshmi; An, Steven S.; Berkowitz, Dan; Baraban, Jay M.; Das, Samarjit
• Is Part Of: Hypertension. Volume 78:Issue 3(2021)
• Page Start: 831
• Page End: 839
• Publication Date: 2021-07-26
• Subjects: aorta -- cardiovascular diseases -- microRNA degradation -- risk factors -- vascular smooth muscle -- vasopressin; Hypertension -- Periodicals; Hypertension -- Treatment -- Periodicals; 616.132005
• DOI: 10.1161/HYPERTENSIONAHA.120.16690
• Languages: English
• ISSNs: 0194-911X

Abstract

Abstract : Supplemental Digital Content is available in the text. 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.