Kanglexin protects against cardiac fibrosis and dysfunction in mice by TGF-β1/ERK1/2 noncanonical pathway

Abstract

Cardiac fibrosis is a common pathological manifestation accompanied by various heart diseases, and antifibrotic therapy is an effective strategy to prevent diverse pathological processes of the cardiovascular system. We currently report the pharmacological evaluation of a novel anthraquinone compound (1,8-dihydroxy-6-methyl-9,10-anthraquinone-3-oxy ethyl succinate) named Kanglexin (KLX), as a potent cardioprotective agent with antifibrosis activity. Our results demonstrated that the administration of KLX by intragastric gavage alleviated cardiac dysfunction, hypertrophy, and fibrosis induced by transverse aortic constriction (TAC) surgical operation. Meanwhile, KLX administration relieved endothelial to mesenchymal transition of TAC mice. In TGF β1-treated primary cultured adult mouse cardiac fibroblasts (CFs) and human umbilical vein endothelial cells (HUVECs), KLX inhibited cell proliferation and collagen secretion. Also, KLX suppressed the transformation of fibroblasts to myofibroblasts in CFs. Further studies revealed that KLX-mediated cardiac protection was due to the inhibitory role of TGF-β1/ERK1/2 noncanonical pathway. In summary, our study indicates that KLX attenuated cardiac fibrosis and dysfunction of TAC mice, providing a potentially effective therapeutic strategy for heart pathological remodeling.

New Insights into the Functions of MicroRNAs in Cardiac Fibrosis: From Mechanisms to Therapeutic Strategies

“…In non-canonical responses, three pathways (PI3K/Akt, RhoA-ROCK axis, and MAPK cascades) can be directly activated by TGF-β [ 33 ]. A few studies reported that TGF-β1 regulated cardiac fibrosis through the activation of the non-canonical responses [ 76 ]. Tao et al demonstrated that miRNA-29a could act as a key regulator to suppress the proliferation of cardiac fibroblasts by targeting the VEGF-A/MAPK signaling pathway [ 41 ].…”

The association between circulatory, local pancreatic PCSK9 and type 2 diabetes mellitus: The effects of antidiabetic drugs on PCSK9

“…Kanglexin, a synthetic anthraquinone, was found to possess higher biological activity and solubility but lower toxicity than natural anthraquinone compounds [ 169 ]. Kanglexin reportedly affords various cardiovascular benefits, such as preventing myocardial injury and cardiac insufficiency after myocardial infarction through the NLRP3 pathway [ 170 ]; inhibiting myocardial fibrosis and cardiac remodelling through TGF-β1/ERK1/2 noncanonical pathway [ 171 ]; and reversing myocardial senescence by binding to the ubiquitin-like domain of Parkin, a key regulatory protein of mitochondrial autophagy [ 169 ]. A recent study revealed that kanglexin promoted angiogenesis and wound healing by stimulating the FGFR1/ERK signalling pathway, indicating potential therapeutic effects in diabetic foot syndrome [ 172 ].…”