Dysregulation of mitochondrial dynamics mediated aortic perivascular adipose tissue-associated vascular reactivity impairment under excessive fructose intake.

Excessive fructose intake presents the major risk factor for metabolic cardiovascular disease. Perivascular adipose tissue (PVAT) is a metabolic tissue and possesses a paracrine function in regulating aortic reactivity. However, whether and how PVAT alters vascular function under fructose overconsumption remains largely unknown. In this study, male Sprague-Dawley rats (8 weeks old) were fed a 60% high fructose diet (HFD) for 12 weeks. Fasting blood sugar, insulin, and triglycerides were significantly increased by HFD intake. Plasma adiponectin was significantly enhanced in the HFD group. The expression of uncoupling protein 1 (UCP1) and mitochondrial mass were reduced in the aortic PVAT of the HFD group. Concurrently, the expression of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) and mitochondrial transcription factor A (TFAM) were suppressed. Furthermore, decreased fusion proteins (OPA1, MFN1, and MFN2) were accompanied by increased fission proteins (FIS1 and phospho-DRP1). Notably, the upregulated α-smooth muscle actin (α-SMA) and osteocalcin in the PVAT were concurrent with the impaired reactivity of aortic contraction and relaxation. Coenzyme Q10 (Q, 10 mg/100 mL, 4 weeks) effectively reversed the aforementioned events induced by HFD. Together, these results suggested that the dysregulation of mitochondrial dynamics mediated HFD-triggered PVAT whitening to impair aortic reactivity. Fortunately, coenzyme Q10 treatment reversed HFD-induced PVAT whitening and aortic reactivity.

High fructose induced osteogenic differentiation of human valve interstitial cells via activating PI3K/AKT/mitochondria signaling.

BACKGROUND: Aortic valve stenosis (AS) is a common, lethal cardiovascular disease. There is no cure except the valve replacement at last stage. Therefore, an understanding of the detail mechanism is imperative to prevent and intervene AS. Metabolic syndrome (MetS) is one of the major risk factors of AS whereas fructose overconsuming tops the list of MetS risk factors. However, whether the fructose under physiological level induces AS is currently unknown. METHODS: The human valve interstitial cells (hVICs), a crucial source to develop calcification, were co-incubated with fructose at 2 or 20 mM to mimic the serum fructose at fasting or post-fructose consumption, respectively, for 24 h. The cell proliferation was evaluated by WST-1 assays. The expressions of osteogenic and fibrotic proteins, PI3K/AKT signaling, insulin receptor substrate 1 and mitochondrial dynamic proteins were detected by Western blot analyses. The mitochondrial oxidative phosphorylation (OXPHOS) was examined by Seahorse analyzer. RESULTS: hVICs proliferation was significantly suppressed by 20 mM fructose. The expressions of alkaline phosphatase (ALP) and osteocalcin were enhanced concurrent with the upregulated PI3K p85, AKT, phospho(p)S473-AKT, and pS636-insulin receptor substrate 1 (p-IRS-1) by high fructose. Moreover, ATP production capacity and maximal respiratory capacity were enhanced in the high fructose groups. Synchronically, the expressions of mitochondrial fission 1 and optic atrophy type 1 were increased. CONCLUSIONS: These results suggested that high fructose stimulated the osteogenic differentiation of hVICs via the activation of PI3K/AKT/mitochondria signaling at the early stage. These results implied that high fructose at physiological level might have a direct, hazard effect on the progression of AS.

Maternal high fructose-induced hippocampal neuroinflammation in the adult female offspring via PPARγ-NF-κB signaling.

The mechanisms beneath the initiation of neuroinflammation are still inconclusive. Growing evidence proposes the maternal effect on the development of neuroinflammation. In this study, we evaluated the upstream regulators and the indices of neuroinflammation in the hippocampi of female offspring at 3 months old. The accumulation of nuclear factor-κB (NF-κB, 65 kDa), a cytokine-encoding transcription factor, was increased in microglia. The enhanced microglial activation was detected in CA1, CA3 and dentate gyrus (DG) HFD group with upregulation of CD11b and ionized calcium binding adaptor molecule 1 (Iba-1). Moreover, proinflammatory cytokines (including TNFα, IL-1ß and IL-6) were significantly increased in HFD group. Peroxisome proliferator-activated receptors γ (PPARγ) is a transcription factor involved in the suppression of NF-κB expression and in encoding endogenous antioxidants (such as catalase and glutathione peroxidases). On the contrary, the expression of nuclear PPARγ was suppressed in hippocampal neurons of the HFD group. In addition, the expressions of glutathione peroxidase 1 (GPx1) was suppressed in HFD group. Oral application with pioglitazone, a PPARγ agonist, effectively ceased the neuroinflammation and reversed the expression of antioxidants in HFD group. Together, these results for the first time demonstrated that maternal HFD triggered the waxing and waning of NF-κB and PPARγ may initiate neuroinflammation in the hippocampus of adult female offspring. Our findings further suggest that PPARγ could be the feasible targets to reprogram the hippocampal impairment induced by maternal HFD.