ArticleWorld journal of gastroenterology2025
Dual therapy with vildagliptin and sacubitril/valsartan alleviates portal hypertension and inhibits soluble epoxide hydrolase in cirrhotic rats.
Article in World journal of gastroenterology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundPortal hypertension (PH), a major complication of cirrhosis, arises from increased intrahepatic resistance and splanchnic vasodilation. Epoxyeicosatrienoic acids (EETs) improve hepatic microcirculation, but their effects are rapidly inactivated by soluble epoxide hydrolase (sEH), an enzyme upregulated in the cirrhotic liver. Inhibiting sEH increases EET levels, reducing portal pressure and fibrosis. Dipeptidyl peptidase-4 inhibitors (DPP4-Is) and angiotensin II blockers have been reported to suppress sEH and enhance EET activity. Angiotensin receptor-neprilysin inhibitors (ARNIs) also lower portal pressure. However, the combined effect of DPP4-I and ARNI on the sEH-EET axis in PH and liver fibrosis remains uninvestigated.
aimTo study the effects of vildagliptin, a DPP4-I and sacubitril/valsartan, an ARNI on PH and liver fibrosis in cirrhotic rats.
methodsTwo rodent models of liver cirrhosis: (1) Choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) diet-fed rats; and (2) Bile duct ligation-induced rats were treated with vildagliptin (10 mg/kg/day), sacubitril/valsartan (30 mg/kg/day), or a combination of both drugs. Hemodynamic parameters, sEH activity, EET levels, vascular remodeling, and fibrosis were assessed using enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction, Western blotting, histology, and immunofluorescence.
resultsIn CDAHFD-fed models, both DPP4-I and ARNI significantly reduced portal pressure in cirrhotic rats by decreasing intrahepatic vascular resistance without affecting systemic hemodynamics. These agents downregulated sEH expression and activity, increasing EET levels, and improved endothelial function
conclusionCombined DPP4-I with ARNI therapy ameliorates PH and fibrosis
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