Inflammation‐induced left ventricular fibrosis is partially mediated by tumor necrosis factor‐α

Abstract

Objective To determine the mechanisms of inflammation‐induced left ventricular (LV) remodeling and effects of blocking circulating tumor necrosis factor alpha (TNF‐α) in a model of systemic inflammation. Methods Seventy Sprague‐Dawley rats were divided into three groups: the control group, the collagen‐induced arthritis (CIA) group, and the anti‐TNF‐α group. Inflammation was induced in the CIA and anti‐TNF‐α groups. Following the onset of arthritis, the anti‐TNF‐α group received the TNF‐α inhibitor, etanercept, for 6 weeks. LV geometry and function were assessed with echocardiography. Circulating inflammatory markers were measured by ELISA and LV gene expression was assessed by comparative TaqMan® polymerase chain reaction. Results The LV relative gene expression of pro‐fibrotic genes, transforming growth factor β (TGFβ) (p = 0.03), collagen I (Col1) (p < 0.0001), and lysyl oxidase (LOX) (p = 0.002), was increased in the CIA group compared with controls, consistent with increased relative wall thickness (p = 0.0009). Col1 and LOX expression in the anti‐TNF‐α group were similar to controls (both, p > 0.05) and tended to be lower compared to the CIA group (p = 0.06 and p = 0.08, respectively), and may, in part, contribute to the decreased relative wall thickness in the anti‐TNF‐α group compared to the CIA group (p = 0.03). In the CIA group, the relative gene expression of matrix metalloproteinase 2 (MMP2) and MMP9 was increased compared to control (p = 0.04) and anti‐TNF‐α (p < 0.0001) groups, respectively. Conclusion Chronic systemic inflammation induces fibrosis and dysregulated LV extracellular matrix remodeling by increasing local cardiac pro‐fibrotic gene expression, which is partially mediated by TNF‐α. Inflammation‐induced LV diastolic dysfunction is likely independent of myocardial fibrosis.

Increased protein phosphatase 5 expression in inflammation-induced left ventricular dysfunction in rats

“…Microvascular inflammation resulting from increased expression of cell adhesion molecules, including VCAM1, promotes leukocyte transmigration [29,30] and enhances ROS production, which are characteristic of an oxidative stress environment [31][32][33]. Supporting this, we previously showed that collagen inoculation increased CD68 expression in LV tissues, showing infiltration of leukocytes [26]. In the present study, PTX3 and iNOS expression was increased in CIA rats, further indicating leukocyte infiltration in the heart tissues and hence local inflammation.…”

“…Circulating CRP concentrations were lower in the CIA + anti-TNF-α group compared to the CIA group (p = 0.05). LV diastolic function was significantly impaired in the CIA and CIA + anti-TNF-α groups (Table 1), as previously reported [24,26]. Briefly, lateral wall e′, e′/a′ and E/e′ were significantly impaired in both groups of rats inoculated with collagen compared to the control group (Table 1).…”

“…In summary, our results show that systemic inflammation induced by collagen inoculation, contributes to microvascular endothelial inflammation and reduced sGC expression, possibly disrupting the NO-sGC-cGMP signaling pathway that increases titin phosphorylation. Our findings suggest that pathological downregulation of NO-sGC-cGMP signaling may not be the primary signal for hypophosphorylation of the titin N2-Bus in HFpEF [3,26], since blocking circulating TNF-α prevented the inflammation-induced effects on NO-sGC-cGMP signaling, but had no effect on LV diastolic dysfunction. Like LV diastolic dysfunction, the inflammation-induced increase in PP5 expression was not prevented by inhibiting circulating TNF-α.…”

“…Blood was centrifuged and serum was collected and stored at − 80 °C. Sandwich enzyme-linked immunosorbent assays (ELISA, Elabscience Biotechnology, USA) were used for duplicate measurements of serum CRP, TNF-α, and IL-6 concentrations [24,26].…”

Tumor Necrosis Factor-α Mediates Inflammation-induced Early-Stage Left Ventricular Systolic Dysfunction

“…5 Adverse extracellular matrix remodeling 16 and hypophosphorylation of the giant spring protein, titin, 17 contribute to passive myocardial stiffness, which affects the ability of the heart to relax during diastole. We have previously shown that rats with CIA have increased profibrotic gene expression LV fibrosis 18 and disrupted expression of genes that regulate titin phosphorylation, 19 showing that systemic inflammation disrupts the passive processes of diastolic function. However, it is not known whether the active process of diastole is affected by the systemic inflammation in rats with CIA.…”