Fibroblast growth factor‐21 protects against fibrosis in hypertensive heart disease

Abstract

FGF21 is an endocrine factor that contributes to multiple pathophysiological processes, mainly via its action as a metabolic regulator and cardioprotective agent. Recent studies have shown increased circulating FGF21 levels in hypertensive patients and in mouse models of hypertension. However, the relevance of FGF21 in hypertensive heart disease has not been addressed. Hypertension was induced by treating 4‐month old WT and Fgf21−/− mice with angiotensin II (AngII) for 1 week, resulting in a similar increase in blood pressure in both genotypes. Plasma FGF21 levels and expression in heart and liver were significantly increased in hypertensive WT mice relative to controls, an effect that was associated with increased expression levels of β‐klotho specifically in the heart. Fgf21−/− mice developed a greater degree of hypertensive heart disease than WT mice, notably characterized by extensive cardiac dysfunction and fibrosis. In vitro and in vivo studies further showed that FGF21 exerted a marked protective effect against cardiac fibrosis. Finally, left ventricle biopsies from human hypertensive heart donors, especially those developing cardiomyopathy, showed a significant increase in FGF21expression compared with normotensive controls, a finding that was associated with significantly enhanced cardiac hypertrophy and fibrosis. We conclude that during hypertension, both systemic and cardiac‐produced FGF21 are induced and act on the heart, protecting it from hypertensive heart disease. Thus, FGF21 acts as key factor in the fibrogenesis associated with hypertensive heart disease. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The protective effect of fibroblast growth factor‐21 in alcoholic cardiomyopathy: a role in protecting cardiac mitochondrial function

“…However, our study goes further as it correlates for the first time the levels of cardiac oxidative stress with FGF21 expression in the myocardium of chronic alcohol consumers. As previously reported in hypertensive patients [13], myocardial FGF21 expression levels also correlate with cardiac hypertrophy and fibrosis, pointing to FGF21 as a potential biomarker for alcoholic cardiomyopathy in humans.…”

“…Cardiac fibrosis is promoted in Fgf21 −/− mice after chronic alcohol consumption Fibrosis develops in the heart under diverse pathological conditions including alcoholic cardiomyopathy [26][27][28] and we previously reported an anti-fibrotic effect of FGF21 in hypertensive heart disease [13]. An analysis of hearts stained using Masson's Trichrome showed evidence of some interstitial fibrosis in alcohol-consuming WT mice, but the highest significant extent of fibrosis occurred in the hearts of Fgf21 −/− mice after chronic alcohol intake ( Figure 3C).…”

“…The heart is both a target and a source of FGF21 [10,11], which acts in an autocrine/ paracrine manner protecting against metabolic, oxidative, and inflammatory cardiac damage [7,12]. FGF21 is also involved in protection against heart hypertrophy [10] and cardiac fibrosis [13]. The protective role of FGF21 in the heart has been reported for distinct diseases including ischaemic heart disease [14], diabetic cardiomyopathy [15], and other clinical conditions [16,17].…”

FGF19 and FGF21 for the Treatment of NASH—Two Sides of the Same Coin? Differential and Overlapping Effects of FGF19 and FGF21 From Mice to Human

“…In addition to the anti-inflammatory and anti-fibrotic effects of FGF21 and FGF19 in the metabolic as well as more mechanistic models of liver disease, several studies support a role in resolving fibrosis independent of BW loss. Administration of FGF21 improves inflammation and fibrosis in diabetic nephropathy (115,116), pulmonary fibrosis induced by bleomycin (115), cardiac fibrosis (117,118), as well as pancreatic fibrosis (119). FGF19 has also shown beneficial effects in diabetic cardiomyopathy improving both cardiac function and decreasing fibrosis (120).…”

FGF21: a promising therapeutic agent for alcoholic cardiomyopathy?†

“…On the other hand, FGF21 exerts beneficial effects in diet‐induced obesity, insulin resistance, healthspan, and lifespan [3]. Moreover, several reports identified FGF21 as a promising cardioprotective hormone against pathologic cardiac hypertrophy, myocardial ischemia, and hypertensive heart disease [2,5,6], suggesting that FGF21 can be used as a therapeutic agent to treat cardiac diseases.…”