Candesartan cilexetil ameliorates NOSTRIN-NO dependent portal hypertension in cirrhosis and ACLF

• Published in: European journal of pharmacology Vol. 958; p. 176010
• Main Authors: Vairappan, Balasubramaniyan, Wright, Gavin, M, Sundhar, Ravikumar, T.S.
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 05-11-2023
• Subjects: Acute-on-chronic liver failure; Candesartan cilexetil; Cirrhosis; Cytokines; Endothelial dysfunction; eNOS; Inflammation; Nitric oxide; NOSIP; Nostrin; Portal pressure; Cirrhosis; Candesartan cilexetil; eNOS; Cytokines; Nitric oxide; Endothelial dysfunction; Acute-on-chronic liver failure; NOSIP; Inflammation; Portal pressure; Nostrin
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2023.176010

In decompensated cirrhosis, the severity of portal hypertension (PHT) is associated with increased hepatic endothelial nitric oxide synthase (eNOS) trafficking inducer (Nostrin), but the mechanism remains unclear. AIM: To investigate: (1) Whether in cirrhosis-PHT models, ± superimposed inflammation to mimic acute-on-chronic liver failure (ACLF) modulates hepatic nitric oxide synthase trafficking inducer (NOSTRIN) expression, nitric oxide (NO) synthesis, and/or endothelial dysfunction (ED); and (2) Whether the “angiotensin II type 1 receptor blocker” candesartan cilexetil (CC) affects this pathway. CD-1 mice received intraperitoneal carbon tetrachloride injections (CCl4 15% v/v in corn oil, 0.5 mL/kg) twice weekly for 12 wk to induce cirrhosis. After 12 wk, mice were randomized to receive 2-wk oral administration of CC (8 mg/kg) ± LPS. At sacrifice, plasma (biochemical indicators, cytokines, and angiotensin II) and liver tissues (histopathology, Sirius-red stains, and molecular studies) were analysed. Moreover, Nostrin gene knockdown was tested in human umbilical vein endothelial cells (HUVECs). When compared to naïve animals, CCl4-treated animals showed markedly elevated hepatic Nostrin expression (P < 0.0001), while hepatic peNOS expression (measure of eNOS activity) was significantly reduced (P < 0.05). LPS challenge further increased Nostrin and reduced peNOS expression (P < 0.05 for both) in cirrhotic animals. Portal pressure and subsequent hepatic vascular resistance were also increased in all cirrhotic animals following LPS challenge. In CCl4 ± LPS-treated animals, CC treatment significantly reduced Nostrin (P < 0.05) and increased hepatic cGMP (P < 0.01). NOSIP, caveolin-1, NFκB, and iNOS protein expression were significantly increased in CCl4-treated animals (P < 0.05 for all). CC treatment non-significantly lowered NOSIP and caveolin-1 expression while iNOS and NFκB expression was significantly reduced in CCl4 + LPS-treated animals (P < 0.05 for both). Furthermore, Nostrin knockdown significantly improved peNOS expression and associated NO synthesis and reduced inflammation in HUVECs. This study is the first to indicate a potential mechanistic role for the Nostrin-eNOS-NO pathway in cirrhosis and ACLF development. Moreover, this pathway provides a potential therapeutic target given the ameliorative response to Candesartan treatment.
Proposed mechanism of eNOS regulation through NOSTRIN in ACLF. [Display omitted]
•We observed significantly elevated hepatic NOSTRIN expression and decreased hepatic peNOS expression in ACLF model.•CC treatment reduced hepatic Nostrin expression and increased peNOS expression and thus hepatic NO bioavailability in ACLF.•Candesartan Cilexetil treatment to ACLF rodents also reduced portal pressure and associated hepatic vascular resistance.•siRNA silencing of Nostrin leads to increased peNOS expression and associated increased NO concentration in HUVECs cells.