Up regulated Tmbim1 activation promotes high fat diet (HFD)-induced cardiomyopathy by enhancement of inflammation and oxidative stress

The prevalence of cardiomyopathy due to metabolic stress has up-regulated dramatically; nevertheless, its molecular mechanisms remain unclear. Here we suggested that transmembrane BAX inhibitor motif-containing 1 (Tmbim1) is down-regulated in the hearts of mice fed with high fat diet (HFD). We provided evidence that Tmbim1 knockout (KO) accelerated HFD-induced metabolic disorders in mice, as supported by the remarkable increase of fasting serum glucose and insulin levels. HFD-induced cardiac dysfunctions were greatly intensified by the loss of Tmbim1, along with higher levels of lactate dehydrogenase (LDH) and creatine kinase (CK) in serum. In addition, Tmbim1 deletion significantly enhanced lipid accumulation in heart of mice administrated with HFD. Furthermore, Tmbim1 knockout reinforced myocardial inflammation, evidenced by increasing the expression of pro-inflammatory cytokines (interleukin 1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α)), and the activation of nuclear factor-κB (NF-κB) signaling pathway. Tmbim1 deficiency strengthened oxidative damage in hearts of HFD-fed mice, accompanied with a significant reduction of nuclear factor-erythroid 2 related factor 2 (Nrf-2) pathway. In palmitate (PA)-treated primary cardiomyocytes, Tmbim1 ablation markedly enhanced cell inflammation and oxidative stress, which were abolished by the suppression of ROS generation and NF-κB activation. Taken together, these findings suggested that Tmbim1 might be a key suppressor of metabolic stress-induced cardiomyopathy, which could be a promising target for the treatment of metabolic syndrome-triggered myocardial damage and heart failure. •Tmbim1 deletion exacerbates metabolic syndrome in HFD-fed mice.•Tmbim1 knockout aggravates HFD-induced cardiac inflammation and oxidative stress.•Tmbim1-regulated cardiac injury is tightly associated with inflammation and oxidative stress in PA-treated primary cardiomyocytes.