TY - JOUR
T1 - Gender Difference in Damage-Mediated Signaling Contributes to Pulmonary Arterial Hypertension
AU - Rafikov, Ruslan
AU - Nair, Vineet
AU - Sinari, Shripad
AU - Babu, Harini
AU - Sullivan, Jennifer C.
AU - Yuan, Jason X.J.
AU - Desai, Ankit A.
AU - Rafikova, Olga
N1 - Funding Information:
The authors would like to thank Dr. S.M. Black for providing rat lung samples, PAEC line, and equipment. This work was supported by NIH grants R01HL133085 (O.R.), Arizona Health Sciences Center Career Development Award (O.R.), R01HL132918 (R.R.), and Scientist Development Grant (14SDG20480354) from the American Heart Association National Office (R.R.).
Publisher Copyright:
© 2019, Mary Ann Liebert, Inc., publishers.
PY - 2019/11/1
Y1 - 2019/11/1
N2 - Aims: Pulmonary arterial hypertension (PAH) is a progressive lethal disease with a known gender dimorphism. Female patients are more susceptible to PAH, whereas male patients have a lower survival rate. Initial pulmonary vascular damage plays an important role in PAH pathogenesis. Therefore, this study aimed at investigating the role of gender in activation of apoptosis/necrosis-mediated signaling pathways in PAH. Results: The media collected from pulmonary artery endothelial cells (PAECs) that died by necrosis or apoptosis were used to treat naive PAECs. Necrotic cell death stimulated phosphorylation of toll-like receptor 4, accumulation of interleukin 1 beta, and expression of E-selectin in a redox-dependent manner; apoptosis did not induce any of these effects. In the animal model of severe PAH, the necrotic marker, high mobility group box 1 (HMGB1), was visualized in the pulmonary vascular wall of male but not female rats. This vascular necrosis was associated with male-specific redox changes in plasma, activation of the same inflammatory signaling pathway seen in response to necrosis in vitro, and an increased endothelial-leukocyte adhesion in small pulmonary arteries. In PAH patients, gender-specific changes in redox homeostasis correlated with the prognostic marker, B-type natriuretic peptide. Males had also shown elevated circulating levels of HMGB1 and pro-inflammatory changes. Innovation: This study discovered the role of gender in the initiation of damage-associated signaling in PAH and highlights the importance of the gender-specific approach in PAH therapy. Conclusion: In PAH, the necrotic cell death is augmented in male patients compared with female patients. Factors released from necrotic cells could alter redox homeostasis and stimulate inflammatory signaling pathways.
AB - Aims: Pulmonary arterial hypertension (PAH) is a progressive lethal disease with a known gender dimorphism. Female patients are more susceptible to PAH, whereas male patients have a lower survival rate. Initial pulmonary vascular damage plays an important role in PAH pathogenesis. Therefore, this study aimed at investigating the role of gender in activation of apoptosis/necrosis-mediated signaling pathways in PAH. Results: The media collected from pulmonary artery endothelial cells (PAECs) that died by necrosis or apoptosis were used to treat naive PAECs. Necrotic cell death stimulated phosphorylation of toll-like receptor 4, accumulation of interleukin 1 beta, and expression of E-selectin in a redox-dependent manner; apoptosis did not induce any of these effects. In the animal model of severe PAH, the necrotic marker, high mobility group box 1 (HMGB1), was visualized in the pulmonary vascular wall of male but not female rats. This vascular necrosis was associated with male-specific redox changes in plasma, activation of the same inflammatory signaling pathway seen in response to necrosis in vitro, and an increased endothelial-leukocyte adhesion in small pulmonary arteries. In PAH patients, gender-specific changes in redox homeostasis correlated with the prognostic marker, B-type natriuretic peptide. Males had also shown elevated circulating levels of HMGB1 and pro-inflammatory changes. Innovation: This study discovered the role of gender in the initiation of damage-associated signaling in PAH and highlights the importance of the gender-specific approach in PAH therapy. Conclusion: In PAH, the necrotic cell death is augmented in male patients compared with female patients. Factors released from necrotic cells could alter redox homeostasis and stimulate inflammatory signaling pathways.
KW - gender difference
KW - inflammation
KW - necrosis
KW - pulmonary hypertension
UR - http://www.scopus.com/inward/record.url?scp=85067961982&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85067961982&partnerID=8YFLogxK
U2 - 10.1089/ars.2018.7664
DO - 10.1089/ars.2018.7664
M3 - Article
C2 - 30652485
AN - SCOPUS:85067961982
SN - 1523-0864
VL - 31
SP - 917
EP - 932
JO - Antioxidants and Redox Signaling
JF - Antioxidants and Redox Signaling
IS - 13
ER -