AS-IV and Tan IIA significantly inhibited excessive collagen cross-linking and reduced cardiac collagen deposition in infarcted hearts by downregulating the CTR1/ATOX1/LOX axis.
AS-IV combined with Tan IIA attenuates cardiac fibrosis and adverse remodeling post-MI in mice by inhibiting the CTR1/ATOX1/LOX axis-mediated collagen cross-linking.
Purpose: This study aims to elucidate the molecular mechanism underlying the therapeutic effect of AS-IV in combination with Tan IIA in ameliorating cardiac fibrosis by inhibiting excessive collagen cross-linking following myocardial infarction (MI). Methods: MI model mice were administered AS-IV and Tan IIA for a duration of four weeks. After the treatment was completed, serum and cardiac specimens were collected from the mice to assess cardiac collagen fiber deposition, collagen cross-linking, cardiac function, copper homeostasis, lysyl oxidase (LOX) content, and the expression of related molecules. Meanwhile, utilizing an in vitro model of myofibroblasts and employing CTR1 overexpression or siRNA-mediated CTR1 silencing and recombinant LOX, we systematically investigated the effects of AS-IV and Tan IIA on key phenotypic features in myofibroblasts, including cross-linking and copper levels. Results: Our results demonstrate that AS-IV and Tan IIA significantly inhibited excessive collagen cross-linking in infarcted hearts, reduced cardiac collagen deposition, and consequently attenuated adverse cardiac remodeling while preserving cardiac function. Mechanistically, AS-IV and Tan IIA suppress intracellular copper accumulation by downregulating the CTR1/ATOX1 axis in the copper transport pathway within myofibroblasts. This downregulation subsequently reduces both the expression and enzymatic activity of LOX, a copper-dependent enzyme, thereby inhibiting excessive collagen cross-linking in these cells. Moreover, AS-IV and Tan IIA demonstrate potential in restoring abnormal copper homeostasis after myocardial infarction and modulating copper distribution within myofibroblasts. Conclusion: AS-IV and Tan IIA attenuate collagen cross-linking in myofibroblasts by downregulating the CTR1/ATOX1/LOX axis, thereby reducing aberrant collagen cross-linking and deposition in the infarcted heart and ultimately inhibiting cardiac fibrosis. The illustration consists of two main sections: Experimental program and Mechanism. The Experimental program section is depicted with a hexagonal arrangement of elements. It includes copper levels, LOX content and activity, cardiac function, hydroxyproline content, CTR1/ATOX1/LOX axis related-proteins and cardiac remodeling. Each element is represented with icons and text indicating its role in the program. The Mechanism section illustrates the process of myocardial infarction leading to cardiac fibrosis. It shows the interaction of AS-IV/TanIIA with CTR1, copper and ATOX1, affecting LOX activity. The diagram depicts excessive collagen deposition, crosslinking and difficulty in degradation, contributing to cardiac fibrosis. Arrows indicate the increase in post-infarction cardiac myofibroblasts and inhibition effects in AS-IV/TanIIA treatment.Diagram showing experimental program and mechanism of cardiac fibrosis and myocardial infarction. Keywords: myocardial fibrosis, cross-linking, lysyl oxidase, copper ion transport
Wang et al. (Mon,) conducted a other in Myocardial infarction and cardiac fibrosis. Astragaloside IV (AS-IV) in combination with Tanshinone IIA (Tan IIA) was evaluated on Cardiac collagen fiber deposition, collagen cross-linking, cardiac function, copper homeostasis, and LOX content. AS-IV and Tan IIA significantly inhibited excessive collagen cross-linking and reduced cardiac collagen deposition in infarcted hearts by downregulating the CTR1/ATOX1/LOX axis.