The crystallin alpha B (HSPB5)-tripartite motif containing 33 (TRIM33) axis mediates myocardial fibrosis induced by angiotensinogen II through transforming growth factor-β (TGF-β1)-Smad3/4 signaling

Abstract

Myocardial fibrosis, a common pathological manifestation of cardiac remodeling (CR), often leads to heart failure (HF) and even death. The underlying molecular mechanism of the role of TRIM33 in Ang II–induced myocardial fibrosis is not fully understood. We found that TRIM33 was specifically upregulated in CFs and myocardial tissue after Ang II stimulation. Adult mice induced by Ang II were used as in vivo models, and Ang II–induced neonatal mouse primary cardiac fibroblasts (CFs) were used as in vitro models. The level of CF fibrosis in vitro was assessed by CF proliferation, migration, activation and extracellular matrix (ECM) synthesis. In addition, Masson staining, the heart weight/body weight (HW/BW) ratio and echocardiography were used to evaluate the in vivo effect of TRIM33. TRIM33 expression was specifically upregulated in CFs and myocardial tissue after Ang II stimulation. In in vitro experiments, we found that TRIM33 knockdown promoted Ang II–induced CF proliferation, while TRIM33 overexpression weakened Ang II–induced CF proliferation, migration, activation and collagen synthesis. Mechanistically, we showed that TRIM33, negatively regulated by HSPB5, mediated its antifibrotic effect by inhibiting the activation of TGF-β1 and its downstream genes, Smad3 and Smad4. Finally, TRIM33 overexpression suppressed fibrosis and promoted cardiac repair and functional recovery in Ang II–induced mice. Our results clearly establish that TRIM33 limits cardiac fibrosis by hindering CF proliferation, migration, activation and collagen synthesis. Enhancing these beneficial functions of TRIM33 by a targeting vector might be a novel therapeutic strategy for CR.

Tripartite motif containing 33 demonstrated anticancer effect by degrading c‑Myc: Limitation of glutamine metabolism and proliferation in endometrial carcinoma cells

“…The TRIM33 gene is on human chromosome 1p13 and belongs to a sub-family of chromatin binding TRIM proteins. The abnormal expression of TRIM33 is associated with the occurrence of human diseases, such as psoriasis ( 22 ), myocardial fibrosis ( 23 ) and types of cancer ( 24 ). The current study is the first, to the best of the authors' knowledge, to demonstrate that TRIM33 could suppress EC cell proliferation, migration and invasion and that these effects were dependent on inhibition of c-Myc, which is often highly expressed and serves pro-survival activity in cancer cells ( 17 , 18 ).…”

KLF9 positively regulates TRIM33 to inhibit abnormal synovial fibroblast proliferation, migration as well as inflammation in rheumatoid arthritis

“…After stimulation by angiotensinogen II (Ang II), the expression of TRIM33 was specifically fortified in primary cardiac fibroblasts and myocardial tissues of newborn mice. Overexpression of TRIM33 inhibited the fibrosis induced by Ang II in mice and accelerated cardiac repair, functional recovery, and restricted cardiac fibrosis 7 . TRIM33 was overexpressed in alveolar macrophages and fibroblasts in idiopathic pulmonary fibrosis patients and fibrotic lungs of rodents.…”

“…Overexpression of TRIM33 inhibited the fibrosis induced by Ang II in mice and accelerated cardiac repair, functional recovery, and restricted cardiac fibrosis. 7 TRIM33 was overexpressed in alveolar macrophages and fibroblasts in idiopathic pulmonary fibrosis patients and fibrotic lungs of rodents. TRIM33 gene knockout made mice sensitive to bleomycin (BLM)‐induced fibrosis, and AdCre‐TRIM33 inhibition aggravated BLM‐induced pulmonary fibrosis in mice.…”

CircBCL2L13 attenuates cardiomyocyte oxidative stress and apoptosis in cardiac ischemia‒reperfusion injury via miR‐1246/PEG3 signaling

“…[13] Furthermore, a series of in vivo and in vitro studies have confirmed that the dysregulation of circRNAs mediates the pathological processes of different diseases, including proliferation, apoptosis, oxidative stress, and inflammation. [14,15] Several reports have clarified the crucial role of circRNAs in the process of reperfusion damage. For example, circUCK2 expression is dysregulated after cerebral I/R, and overexpression of circUCK2 can reduce apoptosis during reperfusion damage.…”