geranylgeranylacetone and Fibrosis

Fibrosis is a response to ongoing cellular injury, disruption, and tissue remodeling, the pathogenesis of which is unknown, and is characterized by extracellular matrix deposition. The antifibrotic effect of Geranylgeranylacetone (GGA), as an inducer of Heat shock protein 70 (HSP70), in liver, kidney and pulmonary fibrosis has been supported by multiple preclinical evidence. However, despite advances in our understanding, the precise roles of HSP70 in fibrosis require further investigation. The purpose of this study was to investigate whether GGA could participate in the progression of pulmonary fibrosis in mice through apoptosis, oxidative stress and inflammation.. B-cell lymphoma-2(Bcl-2) and Bcl2-Associated X (Bax) are two proteins related to apoptosis. Anti-apoptotic factor Bcl-2 and pro-apoptotic factor Bax are often involved in the apoptotic process in the form of dimer. Immunofluorescence and Western blot results showed that bleomycin (BLM) and transforming growth factor-β (TGF-β) inhibited Bcl-2 expression and promoted Bax expression in vitro and in vivo, respectively. In contrast, GGA treatment reverses this change. Reactive oxygen species (ROS), Malondialdehyde (MDA) and superoxide dismutase (SOD) are markers of oxidative stress, which often reflect oxidative injury of cells. The detection of ROS, MDA and SOD expression showed that TGF-β and BLM treatment could significantly promote oxidative stress, while GGA treatment could alleviate oxidative stress damage. In addition, BLM significantly elevated Tumor necrosis factor-α(TNF-α), Interleukin1β (IL-1β) and Interleukin 6 (IL-6), while scutellarin reversed the above alterations except for that of GGA.. Taken together, GGA suppressed apoptotic, oxidative stress and inflammation in BLM-induced pulmonary fibrosis.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Bleomycin; Fibrosis; Inflammation; Lung; Mice; Oxidative Stress; Pneumonia; Pulmonary Fibrosis; Reactive Oxygen Species; Superoxide Dismutase; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Atrial fibrillation (AF) is the commonest arrhythmia. Studies have shown that atrial tachypacing (artificial persistent AF) causes electrical remodelling. This is characterised by the shortening of the atrial effective refractory period (ERP), in which reduction in L-type Ca(2+) channel current plays an essential part. Atrial fibrosis, a feature of structural remodelling, is induced by continuous infusion of angiotensin II, and has been associated with conduction delay in atria, which promotes AF. Acute atrial ischaemia, frequently observed during development of acute coronary syndrome, has been associated with atrial conduction heterogeneity, which also promotes AF. Induction of heat shock proteins (Hsp72 and Hsp27) by hyperthermia and/or geranylgeranylacetone has demonstrated to protect the heart against such atrial remodelling. The potent protective role of Hsp72 and Hsp27 against clinical AF in patients who underwent open heart surgery has been shown. Taken together, interventions that induce heat shock responses (including induction of Hsp72 and Hsp27) may prevent newly developed AF and delay the progression of paroxysmal AF to persistent AF.

Topics: Animals; Atrial Fibrillation; Diterpenes; Dogs; Fever; Fibrosis; Heart Atria; HSP27 Heat-Shock Proteins; HSP72 Heat-Shock Proteins; Humans

Although heat shock protein 72 kDa (HSP72) protects tubular epithelium from a variety of acute insults, its role in chronic renal injury and fibrosis is poorly characterized. In this study, we tested the hypothesis that HSP72 reduces apoptosis and epithelial-to-mesenchymal transition (EMT), important contributors to tubular cell injury in vitro and in vivo. In rats, orally administered geranylgeranylacetone (GGA), an agent that selectively induces HSP72, markedly reduced both apoptosis and cell proliferation in tubular epithelium and decreased both interstitial fibroblast accumulation and collagen I deposition after unilateral ureteric obstruction, a model of chronic renal tubulointerstitial fibrosis and dysfunction. In cultured renal NRK52E cells, exposure to TGF-beta1 induced EMT and apoptosis, major causes of renal fibrosis and tubular atrophy, respectively. Exposure to a pan-caspase inhibitor (ZVAD-FMK) prevented TGF-beta1-induced apoptosis but did not reduce EMT. In contrast, selective HSP72 expression in vitro inhibited EMT caused by TGF-beta1 as indicated by preserving the E-cadherin expression level and alpha-smooth muscle actin induction. Small interfering RNA directed against HSP72 blocked the cytoprotective effects of HSP72 overexpression on EMT in TGF-beta1-exposed cells. Taken together, our data indicate that HSP72 ameliorates renal tubulointerstitial fibrosis in obstructive nephropathy by inhibiting both renal tubular epithelial cell apoptosis and EMT.

Topics: Amino Acid Chloromethyl Ketones; Animals; Apoptosis; Cell Line; Cell Proliferation; Cell Transdifferentiation; Diterpenes; Epithelial Cells; Fibrosis; HSP72 Heat-Shock Proteins; Kidney Failure, Chronic; Kidney Tubules, Proximal; Male; Mesenchymal Stem Cells; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta1