Vitamin D Deficiency Accelerates Coronary Artery Disease Progression in Swine

Abstract

Objective-The role of vitamin D deficiency in coronary artery disease (CAD) progression is uncertain. Chronic inflammation in epicardial adipose tissue (EAT) has been implicated in the pathogenesis of CAD. However, the molecular mechanism underlying vitamin D deficiency-enhanced inflammation in the EAT of diseased coronary arteries remains unknown. We examined a mechanistic link between 1,25-dihydroxyvitamin D-mediated suppression of nuclear factor-κB (NF-κB) transporter, karyopherin α4 (KPNA4) expression and NF-κB activation in preadipocytes. Furthermore, we determined whether vitamin D deficiency accelerates CAD progression by increasing KPNA4 and nuclear NF-κB levels in EAT. Approach and Results-Nuclear protein levels were detected by immunofluorescence and Western blot. Exogenous KPNA4 was transported into cells by a transfection approach and constituted lentiviral vector. Swine were administered vitamin D-deficient or vitamin D-sufficient hypercholesterolemic diet. After 1 year, the histopathology of coronary arteries and nuclear protein expression of EAT were assessed. 1,25-dihydroxyvitamin D inhibited NF-κB activation and reduced KPNA4 levels through increased vitamin D receptor expression. Exogenous KPNA4 rescued 1,25-dihydroxyvitamin D-dependent suppression of NF-κB nuclear translocation and activation. Vitamin D deficiency caused extensive CAD progression and advanced atherosclerotic plaques, which are linked to increased KPNA4 and nuclear NF-κB levels in the EAT. Conclusions-1,25-dihydroxyvitamin

Role of Vitamin D in Cardiovascular Diseases

“…Low levels of vitamin D have been associated with increased risk of CVD such as coronary artery disease (CAD) [5], myocardial infarction (MI) [6–7], hypertrophy [8], cardiomyopathy [9–10], fibrosis [11–12], heart failure (HF) [13–14]. In addition, deficiency of vitamin D has been found in arterial diseases, including aneurysm [15–16], peripheral arterial disease (PAD) [17–19], arterial calcification [20], hypertension (HTN) [21–22] and atherosclerosis [23] (Figures 2 and 3).…”

Duck karyopherin α4 (duKPNA4) is involved in type I interferon expression and the antiviral response against Japanese encephalitis virus

“…Mammalian KPNA4 plays a role in regulating the nuclear transportation of type I IFN transcription factors, thereby triggering the expression of type I IFN and the subsequent immune response against virus infection (Zhu et al, 2015;Chen et al, 2016;Li et al, 2018). However, the role of avian KPNA4 in type I IFN expression was unknown.…”

“…Among the identified KPNAs, KPNA4 in the α3 subfamily is involved in the innate immune response against viral infection Ye et al, 2017). Several KPNA4 orthologues from different species including humans (Köhler et al, 1997), mice (Mihalas et al, 2015), pigs (Chen et al, 2016) and chickens (Caldwell et al, 2005) have been identified. In mammals, human KPNA4, a specific adaptor molecule, mediates the nuclear import of interferon (IFN) transcriptional regulators, such as NF-κB p50/p65 heterodimers and IFN regulatory factor (IRF) 3, thereby regulating type I IFN-mediated immune responses (Canton et al, 2018;Shaw et al, 2005).…”

Vitamin D controls resistance artery function through regulation of perivascular adipose tissue hypoxia and inflammation

“…TNFα, IL-6, MCP-1 and pentraxin 3) in epicardial adipose tissue biopsy samples from human patients with coronary artery disease (24). Mechanistically, vitamin D controls inflammatory signaling pathways through regulation of key molecules including importin-α3 (karyopherin-α4), NF-κβ, and suppressor of cytokine signaling 3 (SOCS3) (9, 25, 26). …”