Astragaloside IV Prevents Cardiac Remodeling in the Apolipoprotein E-Deficient Mice by Regulating Cardiac Homeostasis and Oxidative Stress

Abstract

Background: Hypercholesterolemia is a risk factor for the development of cardiac hypertrophy. Astragaloside IV (AST-IV) possesses cardiovascular protective properties. We hypothesize that AST-IV prevents cardiac remodeling with hypercholesterolemia via modulating tissue homeostasis and alleviating oxidative stress. Methods: The ApoE^-/- mice were treated with AST-IV at 1 or 10 mg/kg for 8 weeks. The blood lipids tests, echocardiography, and TUNEL were performed. The mRNA expression profile was detected by real-time PCR. The myocytes size and number, and the expressions of proliferation (ki67), senescence (p16^INK4a), oxidant (NADPH oxidase 4, NOX4) and antioxidant (superoxide dismutase, SOD) were observed by immunofluorescence staining. Results: Neither 1 mg/kg nor 10 mg/kg AST-IV treatment could decrease blood lipids in ApoE^-/- mice. However, the decreased left ventricular ejection fraction (LVEF) and fractional shortening (FS) in ApoE^–/– mice were significantly improved after AST-IV treatment. The cardiac collagen volume fraction declined nearly in half after AST-IV treatment. The enlarged myocyte size was suppressed, and myocyte number was recovered, and the alterations of genes expressions linked to cell cycle, proliferation, senescence, p53-apoptosis pathway and oxidant-antioxidants in the hearts of ApoE^-/- mice were reversed after AST-IV treatment. The decreased ki67 and increased p16^INK4a in the hearts of ApoE^-/- mice were recovered after AST-IV treatment. The percentages of apoptotic myocytes and NOX4-positive cells in AST-IV treated mice were decreased, which were consistent with the gene expressions. Conclusion: AST-IV treatment could prevent cardiac remodeling and recover the impaired ventricular function induced by hypercholesterolemia. The beneficial effect of AST-IV might partly be through regulating cardiac homeostasis and anti-oxidative stress.

Natural Drugs as a Treatment Strategy for Cardiovascular Disease through the Regulation of Oxidative Stress

“…As-IV has also been reported to inhibit ROS and NADPH production by upregulating PGC-1 α and TFAM, as well as to promote mitochondrial autophagy and mitochondrial biogenesis, contributing to the protection of damaged mitochondria through its antioxidant activity [ 135 ]. As-IV can also reduce the activities of CPK and LDH, reduce the loss of mitochondrial membrane potential, and ultimately slow down cardiomyocyte apoptosis [ 136 – 138 ].…”

Astragaloside IV Exerts a Myocardial Protective Effect against Cardiac Hypertrophy in Rats, Partially via Activating the Nrf2/HO-1 Signaling Pathway

“…Moreover, the specific protective effects of ASIV may oppose processes such as cardiomyocyte hypertrophy, apoptosis, and fibrosis [18–22]. Some studies have suggested that the protective effect of ASIV against cardiac hypertrophy is related to the regulation of cardiac-related signaling pathways, such as inhibition of the TLR4/NF- κ B signaling pathway and the Ca 2+ /CaN signaling pathway and regulation of NF- κ B/PGC-1 α signaling-mediated energy biosynthesis [18, 19, 23, 24]. Other studies have shown that ASIV can protect brain tissue by reducing oxidative stress and mediating related signaling pathways [25].…”

Apolipoprotein E Deficiency Exacerbates Spinal Cord Injury in Mice: Inflammatory Response and Oxidative Stress Mediated by NF-κB Signaling Pathway

“…More specifically, Apoe possesses anti-inflammatory, anti-oxidative and anti-apoptosis properties (Laskowitz et al, 1997 , 1998 ; Kitagawa et al, 2002 ; Hayashi et al, 2009 ; Li X.-Z. et al, 2017 ). For instance, APOE mimetic peptide significantly suppressed microglial activation in rats with SCI.…”