Control of protein function through oxidation and reduction of persulfidated states.

Irreversible oxidation of Cys residues to sulfinic/sulfonic forms typically impairs protein function. We found that persulfidation (CysSSH) protects Cys from irreversible oxidative loss of function by the formation of CysSSO1-3H derivatives that can subsequently be reduced back to native thiols. Reductive reactivation of oxidized persulfides by the thioredoxin system was demonstrated in albumin, Prx2, and PTP1B. In cells, this mechanism protects and regulates key proteins of signaling pathways, including Prx2, PTEN, PTP1B, HSP90, and KEAP1. Using quantitative mass spectrometry, we show that (i) CysSSH and CysSSO3H species are abundant in mouse liver and enzymatically regulated by the glutathione and thioredoxin systems and (ii) deletion of the thioredoxin-related protein TRP14 in mice altered CysSSH levels on a subset of proteins, predicting a role for TRP14 in persulfide signaling. Furthermore, selenium supplementation, polysulfide treatment, or knockdown of TRP14 mediated cellular responses to EGF, suggesting a role for TrxR1/TRP14-regulated oxidative persulfidation in growth factor responsiveness.

Acute effects of device-guided slow breathing on sympathetic nerve activity and baroreflex sensitivity in posttraumatic stress disorder.

Patients with posttraumatic stress disorder (PTSD) have elevated sympathetic nervous system reactivity and impaired sympathetic and cardiovagal baroreflex sensitivity (BRS). Device-guided slow breathing (DGB) has been shown to lower blood pressure (BP) and sympathetic activity in other patient populations. We hypothesized that DGB acutely lowers BP, heart rate (HR), and improves BRS in PTSD. In 23 prehypertensive veterans with PTSD, we measured continuous BP, ECG, and muscle sympathetic nerve activity (MSNA) at rest and during 15 min of DGB at 5 breaths/min ( n = 13) or identical sham device breathing at normal rates of 14 breaths/min (sham; n = 10). Sympathetic and cardiovagal BRS was quantified using pharmacological manipulation of BP via the modified Oxford technique at baseline and during the last 5 min of DGB or sham. There was a significant reduction in systolic BP (by -9 ± 2 mmHg, P < 0.001), diastolic BP (by -3 ± 1 mmHg, P = 0.019), mean arterial pressure (by -4 ± 1 mmHg, P = 0.002), and MSNA burst frequency (by -7.8 ± 2.1 bursts/min, P = 0.004) with DGB but no significant change in HR ( P > 0.05). Within the sham group, there was no significant change in diastolic BP, mean arterial pressure, HR, or MSNA burst frequency, but there was a small but significant decrease in systolic BP ( P = 0.034) and MSNA burst incidence ( P = 0.033). Sympathetic BRS increased significantly in the DGB group (-1.08 ± 0.25 to -2.29 ± 0.24 bursts·100 heart beats-1·mmHg-1, P = 0.014) but decreased in the sham group (-1.58 ± 0.34 to -0.82 ± 0.28 bursts·100 heart beats-1·mmHg-1, P = 0.025) (time × device, P = 0.001). There was no significant difference in the change in cardiovagal BRS between the groups (time × device, P = 0.496). DGB acutely lowers BP and MSNA and improves sympathetic but not cardiovagal BRS in prehypertensive veterans with PTSD. NEW & NOTEWORTHY Posttraumatic stress disorder is characterized by augmented sympathetic reactivity, impaired baroreflex sensitivity, and an increased risk for developing hypertension and cardiovascular disease. This is the first study to examine the potential beneficial effects of device-guided slow breathing on hemodynamics, sympathetic activity, and arterial baroreflex sensitivity in prehypertensive veterans with posttraumatic stress disorder.

Endothelin production in the rabbit collecting ducts of acute renal failure models. An immunohistochemical study.

Endothelin 1 (ET-1) production was examined in the rabbit nephron in acute renal failure (ARF) induced by uranyl acetate administration or by clamping the renal artery. Uranyl acetate dissolved in saline was injected intravenously at a dose of 0.8 mg/kg (n = 12). In the ischemic kidney experiment, 60 min of left renal artery clamping was carried out 1 week after removing the right kidney (n = 8). Plasma and urine concentrations of ET-1 were measured 0, 24, and 48 h after treatment, and immunohistochemical studies of renal tissues obtained 48 h after the experiments were carried out using ET-1 monoclonal antibody. The fractional excretion of ET-1 increased from 10 to 89% at 48 h in the uranyl acetate treated group and from 6 to 15% at 24 h in the renal artery clamping group, suggesting the existence of ET-1 secretion from the nephron in both types of ARF. By immunohistochemical examination, strong ET-1 expression was noted only in the collecting ducts. No staining was observed in other parts of the nephron in both types of ARF. The present study indicates that the increased expression of ET-1 probably reflects production by the collecting ducts in both rabbit ARF models.

Pathophysiological role of magnesium in familial Bartter's syndrome.

We studied three siblings with Bartter's syndrome associated with hypomagnesemia; two of them showing marked hypomagnesemia and the other mild hypomagnesemia. Urinary potassium, sodium and chloride excretions were determined and distal fractional chloride reabsorption and free water clearance on water loading test were compared before and after magnesium supplementation. Baseline urinary potassium and magnesium excretions were elevated in spite of the decreased plasma levels, whereas distal fractional chloride reabsorption and free water clearance were depressed in all patients. Magnesium repletion resulted in significant decrease in urinary potassium, sodium and chloride and subsequent increase in plasma potassium in all patients. However, neither distal fractional chloride reabsorption nor free water clearance was affected. Hypomagnesemia may contribute to urinary potassium wasting and aggravate urinary sodium and chloride wasting in familial Bartter's syndrome by a mechanism independent of the defect in free-water formation by the active reabsorption of chloride in Henle's loop.