RESUMO
Altered bone morphogenic protein (BMP) signaling, independent of BMPR2 mutations, can result in idiopathic pulmonary arterial hypertension (IPAH). Glucose dysregulation can regulate multiple processes in IPAH. However, the role of glucose in BMP antagonist expression in IPAH has not been characterized. We hypothesized that glucose uptake regulates BMP signaling through stimulation of BMP antagonist expression in IPAH. Using human plasma, lung tissue, and primary pulmonary arterial smooth muscle cells (PASMCs), we examined the protein expression of BMP2, BMP-regulated Smads, and Smurf-1 in patients with IPAH and control subjects. Gremlin-1 levels were elevated in patients with IPAH compared with control subjects, whereas expression of BMP2 was not different. We demonstrate increased Smad polyubiquitination in IPAH lung tissue and PASMCs that was further enhanced with proteasomal inhibition. Examination of the Smad ubiquitin-ligase, Smurf-1, showed increased protein expression in IPAH lung tissue and localization in the smooth muscle of the pulmonary artery. Glucose dose dependently increased Smurf-1 protein expression in control PASMCs, whereas Smurf-1 in IPAH PASMCs was increased and sustained. Conversely, phospho-Smad1/5/8 levels were reduced in IPAH compared with control PASMCs at physiological glucose concentrations. Interestingly, high glucose concentrations decreased phosphorylation of Smad1/5/8 in control PASMCs. Blocking glucose uptake had opposing effects in IPAH PASMCs, and inhibition of Smurf-1 activity resulted in partial rescue of Smad1/5/8 activation and cell migration rates. Collectively, these data suggest that BMP signaling can be regulated through BMPR2 mutation-independent mechanisms. Gremlin-1 (synonym: induced-in-high-glucose-2 protein) and Smurf-1 may function to inhibit BMP signaling as a consequence of the glucose dysregulation described in IPAH.
RESUMO
BACKGROUND: Artificial playing surfaces are becoming more common due to decreased cost of maintenance and increased field usability across different environmental conditions. The Fédération Internationale de Football Association (FIFA) has approved newer generation artificial turf for soccer competition at the elite level, but many elite-level athletes prefer to play on natural grass surfaces due to a perceived increase in injury rate, discomfort, and fatigability on artificial turf. HYPOTHESIS: Injury rates and rates of individually categorized types of injury experienced on artificial turf are noninferior to rates of injury on the standard comparator, natural grass, in elite-level Major League Soccer athletes. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Over the course of 4 Major League Soccer seasons (2013-2016), athlete injury data were recorded electronically. Injury data recorded in matches between 2 Major League Soccer teams were then analyzed. Playing surface was known for each venue, and all artificial turf surfaces were rated as 2-star according to FIFA criteria. Incidence rate ratios (Artificial Turf ÷ Natural Grass) were calculated with a 95% CI (α = .05) for both overall injury incidence and individual injury subgroups. A noninferiority margin (δ) of 0.15 was used to determine noninferiority of injury incidence rates. RESULTS: A total of 2174 in-game injuries were recorded during the study period, with 1.54 injuries per game on artificial turf and 1.49 injuries per game on natural grass (incidence rate ratio, 1.033; 95% CI, 0.937-1.139). Within injury subgroups, overall ankle injury, Achilles injury, and ankle fracture were found to have a statistically higher incidence on artificial turf. Artificial turf was found to be noninferior to natural grass for overall foot injury and forefoot injury. No statistically significant differences were found in knee injuries between the 2 surfaces. CONCLUSION: The overall rate of injury on artificial turf was noninferior to that on natural grass. Within individual injury categories, a higher rate of ankle injury was found on artificial turf. No other injury subgroup demonstrated statistically significant differences between surfaces. CLINICAL RELEVANCE: FIFA 2-star rated artificial turf is a viable alternative to natural grass in elite-level soccer competition. Innovative research methods for comparing artificial turf versus natural grass may elucidate relative advantages with respect to player safety.