FRI131 Abrogation Of Transglutaminase 2 In Myeloid Cells Ameliorates Angiotensin II Induced Vascular Stiffness In Female Mice

Disclosure: H. Naz: None. A.R. Aroor: None. A.T. Whaley-Connell: None. J. Guanghong: None. J.L. Hulse: None. C.M. Manrique Acevedo: None. G. Lastra: None. Introduction: Chronic low-grade inflammation and vascular stiffening contribute to cardiovascular disease (CVD) in obese and insulin-resistant women. Under these conditions, inappropriate activation of the renin angiotensin aldosterone system (RAAS) stimulates Transglutaminase 2 (TG2), a ubiquitously expressed enzyme that promotes vascular stiffening and remodeling. Additionally, Th17 cells contribute to CVD development in the setting of RAAS activation. However, it is unclear how TG2 activation mediates maladaptive immune responses associated with vascular stiffening in women. In this study, we hypothesize that TG2 abrogation inhibits Ang II-induced vascular stiffness in females by modulating Th17 immunity. Methods: 12-week-old female mice lacking TG2 expression (MyTG2KO) in myeloid cells, and control littermates (LM) were infused with Ang-II (1.4 mg/kg/day) for 2 weeks (n=4-8 per group). Prior to sacrifice, systolic blood pressure (SBP) was measured by tail-cuff method. Aortic stiffness was assessed by atomic force microscopy of thoracic aorta explants, and TG2 activity was examined by Alexa FluorTM 488 cadaverine. Analysis of Th17 cells in blood, spleen and epididymal fat (epi-fat) was done by flow cytometry. Cytokine bead array was used to measure cytokine levels in serum, RT-PCR was used to analyze cytokines in aortic tissue and TG2 knockdown efficiency in myeloid cells. Immunohistochemistry was used to examine fibrosis in aorta. Results: SBP was decreased in MyTG2KO-Ang-II as compared to LM-Ang-II cohort (129.6±5.6 vs 152.5 ±2 mmHg; p=0.04). TG2 mRNA expression in macrophages was lower in MyTG2KO mice as compared to LM (p=0.002). TG2 activity in aortic tissue increased in LM-Ang-II as compared to LM-saline (p=0.004) but was significantly lower in MyTG2KO-Ang-II mice (p=0.02). Aortic stiffness was lower in MyTG2KO-Ang-II mice relative to LM-Ang-II (4.0±0.6 vs 10.3±2.4 kPa; p=0.02). Compared to LM-Ang-II, MyTG2KO-Ang-II mice also had decreased Th17 lymphocytes (CD4+IL-17A+) in blood (3.5±0.2 vs 5.8 ±0.4 %; p=