RESUMO
Decreased nitric oxide (NO) bioavailability and oxidative stress are hallmarks of endothelial dysfunction and cardiovascular diseases. Although numerous proteins are S-nitrosated, whether and how changes in protein S-nitrosation influence endothelial function under pathophysiological conditions remains unknown. We report that active endothelial NO synthase (eNOS) interacts with and S-nitrosates pyruvate kinase M2 (PKM2), which reduces PKM2 activity. PKM2 inhibition increases substrate flux through the pentose phosphate pathway to generate reducing equivalents (NADPH and GSH) and protect against oxidative stress. In mice, the Tyr656 to Phe mutation renders eNOS insensitive to inactivation by oxidative stress and prevents the decrease in PKM2 S-nitrosation and reducing equivalents, thereby delaying cardiovascular disease development. These findings highlight a novel mechanism linking NO bioavailability to antioxidant responses in endothelial cells through S-nitrosation and inhibition of PKM2.
Assuntos
Substituição de Aminoácidos , Óxido Nítrico Sintase Tipo III/metabolismo , Óxido Nítrico/metabolismo , Piruvato Quinase/metabolismo , Animais , Células Cultivadas , Células Endoteliais , Homeostase , Humanos , Masculino , Camundongos , Óxido Nítrico Sintase Tipo III/genética , Oxirredução , Via de Pentose Fosfato , Ligação ProteicaRESUMO
BACKGROUND: Despite national guideline recommendations, epidermal growth factor receptor mutated (EGFRm) metastatic non-small cell lung cancer (mNSCLC) patients may still receive suboptimal treatment in the first line (1L). This study evaluated 1L therapy initiation in relation to biomarker testing results and time to next-treatment or death (TTNTD) in patients receiving EGFR tyrosine kinase inhibitors (TKIs) versus immunotherapy (IO) or chemotherapy. METHODS: Stage IV EGFRm mNSCLC adults that initiated 1L EGFR TKI (first, second, or third generation), IO ± chemotherapy (IO users), or chemotherapy alone from 5/2017-12/2019 were identified from the Flatiron database. Logistic regression estimated the likelihood of initiating treatment before receiving testing results for each therapy. Median TTNTD was evaluated via Kaplan-Meier analysis. Adjusted hazards ratios (HRs) and 95% CI examining the association of 1L therapy with TTNTD were reported from multivariable Cox proportional-hazards models. RESULTS: Among 758 EGFRm mNSCLC patients, EGFR TKI was used as 1L therapy for 87.3% of patients (n = 662), IO in 8.3% (n = 63), and chemotherapy only in 4.4% (n = 33). The majority of IO (61.9%) and chemotherapy only patients (60.6%) initiated therapy before test results were available, compared to 9.7% of EGFR TKIs. The odds of initiating therapy before receiving test results were higher for IO (OR: 19.6, p < 0.001) and chemotherapy alone (OR: 14.1, p < 0.001) in comparison to EGFR TKIs. Compared to IO and chemotherapy, EGFR TKIs had longer median TTNTD (EGFR TKI: 14.8 months, 95% CI: 13.5-16.3; IO: 3.7 months, 95% CI 2.8-6.2; chemotherapy: 4.4 months, 95% CI 3.1-6.8, p < 0.001). EGFR TKI patients had significantly lower risk of initiating second-line therapy or death compared to patients on 1L IO (HR: 0.33, p < 0.001) or 1L chemotherapy (HR: 0.34, p < 0.001). CONCLUSIONS: A portion of biomarker testing results were not used to guide 1L therapy. Patients initiating EGFR TKI as 1L therapy had longer TTNTD than IO or chemotherapy.