Angiotensin-II (ANGII) induces hypertension and cardiac hypertrophy, leading to heart failure in humans. ANGII is a potent inductor of oxidative stress, which changes proteins function via oxidative post-translational modifications (oxPTM). Glutaredoxin-1 (Grx) catalyses the removal of an oxPTM, S-glutathionylation, and has been shown to be important in peripheral artery.  However, the role of Grx in ANGII induced cardiac failure is unknown. This project aims to investigate the effect of ANGII infusion in mice that overexpress Grx. 

 

Grx transgenic (TG) and wild-type (WT) littermates (C57Bl6/j, Male, 24.7-30.5g) were implanted with osmotic pumps (Alzet) containing either saline or ANGII (1.1mg/kg/day; s.c, n=4-8.). After 2 weeks, mice were anesthetised with isoflurane (2%) and a pressure-volume catheter (Transonics, 1.2F, 4.5mm) was inserted retrogradely into the left ventricle (LV) via the aorta in a closed chest preparation.  To obtain aortic blood pressure (BP) and LV pressure-volume loops. All values are mean±SEM, compared by 1-way ANOVA.

In WT mice (n=4-8), ANGII increased systolic BP(SBP) (Saline: 95.7±4.0 mmHg vs ANGII: 116.0±5.6mmHg, p<0.05) and diastolic BP(DBP) (Saline: 65.2±3.9mmHg vs ANGII: 82.9±4.0mmHg, p<.05). However, no significant increase in SBP and DBP were observed in TG mice (SBP Saline: 96.8±2.3mmHg vs ANGII: 109.4±6.1mmHg, p=ns) and DBP (Saline: 64.26±2.1 mmHg vs ANGII: 74.58±4.9 mmHg, p=ns) remained constant. Heart rates were not significantly different between the four groups ranging from 560 to 588bpm.  

Although there was an increase in BP in WT ANGII mice, left ventricle end-diastolic/systolic pressure (EDP/ESP) and end systolic volume(ESV) remained unchanged between the four groups.  However, ANGII significantly lowered end diastolic volume (EDV) in TG compared to WT hearts (WT:42.2±2.7uL vs TG:22.4±2.0uL, p<0.05). Hence, stroke volume(SV) was also lowered in TG compared to WT (WT:24.4±3.0uL vs TG:16.4±1.6uL, p<0.05). Yet, these changes had no overall effect on LV cardiac output (ANGII, WT: 13947±1353 mL/min vs. TG: 2191.0±286.2mL/min, p=ns) or stroke work (ANGII, WT: 2191±286 mmHg*uL, vs. 2191.0±286.2mmHg*uL, p=ns). Interestingly, ANGII significantly lowered LV contractile state (Powermax) in response to ANGII in TG compared to WT mice (WT:343467±782502 mmHg*uL/s vs TG:161963±29044 mmHg*ul/s, p<0.05). 

In the control groups, there was no difference in cardiac function between saline treated WT and TG mice. With stroke work (WT: 1719±109 mmHg*uL vs TG: 1341±402mmHg*uL, p=ns), cardiac output (WT: 12004±783 mL/min vs TG: 9227±2237mL/min, p=ns) and stroke volume (Saline: 20.5±0.8uL vs 16.4±1.6uL  , p=ns) remained unchanged between WT and TG mice. 

 

In summary chronic ANGII infusion did not increase blood pressure in mice overexpressing Grx, but lowered pre-load with subsequent lower stroke volume and cardiac contractility. Future studies will find which redox sensitive proteins undergo reversal oxPTM to elicit these functional changes, leading to identification of novel therapeutic targets.