Gastrin ameliorates heart failure and suppresses myocardial remodeling via the JAK2/STAT3 and ERK1/2 pathways

TL;DR

Gastrin helps reduce heart failure and heart tissue changes by blocking specific signaling pathways in mice.

Contribution

Gastrin's protective role in heart failure is linked to JAK2/STAT3 and ERK1/2 pathways via CCK2 receptors.

Findings

Gastrin reduced ISO-induced heart failure and myocardial remodeling in mice.

Gastrin suppressed JAK2/STAT3 and ERK1/2 pathway activation in cardiac tissues.

CCK2R inhibition reversed gastrin's protective effects on heart function and hypertrophy.

Abstract

Previous studies have indicated elevated serum gastrin levels in individuals with HF. However, the association and underlying mechanisms between gastrin and HF remain unclear. This article aims to investigate the effects of gastrin on myocardial remodeling and HF, as well as its potential signal transduction mechanisms.

In vivo studies were initially conducted to investigate the relationship between gastrin and HF, as well as the effects of gastrin on myocardial remodeling and HF. Gastrin levels were measured using ELISA kits to assess their association with ISO-induced HF. Echocardio- graphy, qRT-PCR analysis of hypertrophy (ANP, BNP, β-MHC) and fibrosis markers (COL1, COL3, α-SMA), hematoxylin-eosin staining, and Masson’s trichrome staining were performed to evaluate the impact of gastrin on HF, MH, and fibrosis in mice.Furthermore, the effect of gastrin on cardiomyocyte hypertrophy was investigated in vitro using H9C2 cells, with F-actin staining and qRT-PCR analysis of ANP and BNP employed. Additionally, western blotting (WB) analysis of P-JAK2/JAK2, P-STAT3/STAT3, and P-ERK/ERK in cardiac tissues and cells was used to identify pathways through which gastrin modulates HF and myocardial remodeling.

In vivo study, the ISO-treated mice exhibited significantly increased gastrin levels compared to the control group (P ＜ 0.05). Furthermore, the ISO group showed significant cardiac hypertrophy, characterized by increased heart size, thickened ventricular walls, impaired cardiac function, and expanded fibrotic areas (P ＜ 0.05). In contrast, the gastrin-only group exhibited no significant pathological changes. Co-treatment with gastrin and ISO notably attenuated these pathological changes, whereas CI-988(a CCK2R inhibitor) admini- stration partially reversed gastrin’s protective effects (P ＜ 0.05). In vitro study,the ISO group exhibited a significantly larger cardiomyocyte surface area and elevated expression of hypertrophy-associated biomarkers (ANP and BNP) compared to controls (P ＜ 0.01). Gastrin treatment significantly suppressed these changes (P ＜ 0.01), but this protective effect was partly reversed by the CCK2R antagonist CI-988 (P ＜ 0.05). Additionally, phosphorylation levels of JAK2, STAT3, and ERK were significantly increased in the ISO group (P ＜ 0.05) both in mice cardiac tissues and H9C2 cells. Gastrin treatment suppressed these increases (P < 0.05), an effect diminished by CI-988 (P ＜ 0.05).

Gastrin may exert protective effects against ISO-induced HF and myocardial remodeling by inhibiting the JAK2/STAT3 and ERK1/2 pathways via the CCK2 receptor.

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