Targeting Tumor Necrosis Factor-α Mitigates Glucose Fluctuation-Induced Aortic Valve Fibrosis: Insights From Diabetic Rat Models.

BACKGROUND: Calcific aortic valve disease (CAVD) is a progressive condition characterized by inflammation and fibrous calcification remodeling, with aortic valve fibrosis (AVF) representing the associated subclinical phase. Early intervention with oral medication during the AVF stage may prevent and slow the development and progression of CAVD. Previous studies have demonstrated that individuals with diabetes are at an elevated risk of CAVD and also experience a significantly higher incidence of aortic valve stenosis, which rapidly advances from mild to severe stages. Significantly, the adverse effects of glucose fluctuations (GFs) on cardiovascular diseases exceed those associated with persistent hyperglycemia. Nonetheless, the mechanisms through which GFs contribute to AVF, the early stage of CAVD, remain inadequately understood. Consequently, this study aimed to investigate the inflammatory mechanisms underlying AVF induction in response to fluctuations in glucose levels. METHODS: Diabetic rat models were established through intraperitoneal injection of streptozotocin (STZ). GFs in these diabetic rats were managed by alternating between a Western diet and periods of fasting. Infliximab was administered to inhibit inflammation mediated by tumor necrosis factor-alpha (TNF-α). For the in vivo study, echocardiographic assessments of the aortic valve and left ventricular function were conducted on the diabetic rats after eight weeks. Aortic valves from various groups of rats were dissected to test fibrosis, extracellular matrix remodeling, and variations in inflammatory factors, which were examined using hematoxylin and eosin (HE) staining, modified Movat-Russell pentachrome staining, and immunohistochemical staining, respectively. For the in vitro study, porcine valvular interstitial cell (VIC) cultures were used to establish GF-induced fibrosis, thereby elucidating the underlying inflammatory mechanisms. RESULTS: Our study demonstrated that GFs exacerbate AVF and dysfunction in diabetic patients. This is characterized by increased peak blood flow velocity and peak cross-valve gradient of the aortic valve. Furthermore, we observed intensified TNF-α-mediated inflammatory responses, characterized by the upregulation of T lymphocytes and macrophages, as well as activation of the Janus kinase 1 (JAK1)/signal transducer and activator of transcription 3 (STAT3) pathway. Notably, these pathological processes were ameliorated by the administration of infliximab, resulting in the downregulation of fibrotic and inflammatory markers, as well as improved echocardiographic indices. Our research findings indicate that TNF-α-mediated inflammation exacerbates fibrotic aortic valve processes through GFs, which are mediated by the JAK1/STAT3 signaling pathway. CONCLUSIONS: Targeting TNF-α may serve as a potential therapeutic target to mitigate the progression of inflammation-induced aortic valve damage and fibrosis.