Dual therapy with vildagliptin and sacubitril/valsartan alleviates portal hypertension and inhibits soluble epoxide hydrolase in cirrhotic rats

Abstract

Background: Portal 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.

Aim: To study the effects of vildagliptin, a DPP4-I and sacubitril/valsartan, an ARNI on PH and liver fibrosis in cirrhotic rats.

Methods: Two 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.

Results: In 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 via nitric oxide signaling enhancement. They also suppressed sinusoidal capillarization, pathological angiogenesis, and Hedgehog signaling, while restoring sinusoidal endothelial markers. Additionally, DPP4-I and ARNI attenuated liver fibrosis and stellate cell activation, reducing profibrotic gene expression. These effects were additive by the combination of both drugs. Similar effects were observed in bile duct ligation-induced PH, confirming their therapeutic potential in managing both PH and liver fibrosis through modulation of the sEH-EET pathway.

Conclusion: Combined DPP4-I with ARNI therapy ameliorates PH and fibrosis via sEH suppression and EET restoration, offering a promising treatment strategy for cirrhosis-related PH.

Keywords: Angiogenesis; Animal model; Capillarization; Liver fibrosis; Liver sinusoidal endothelial cell.