Set7 deletion attenuates isoproterenol-induced cardiac fibrosis and delays cardiac dysfunction

Abstract

Cardiovascular diseases are the main cause of death worldwide. Recent studies have revealed the influence of histone-modifying enzymes in cardiac remodeling and heart dysfunction. The Set7 methyltransferase regulates the expression of several genes through the methylation of histones and modulates the activity of non-histone proteins. However, the role of Set7 in cardiac remodeling and heart dysfunction remains unknown. To address this question, wild type (WT) and Set7 knockout (KO) male mice were injected with isoproterenol or saline. WT mice injected with isoproterenol displayed a decrease in Set7 activity in the heart. In addition, WT and Set7 KO mice injected with isoproterenol exhibited cardiac hypertrophy. Interestingly, Set7 deletion exacerbated cardiac hypertrophy in response to isoproterenol, but attenuated myocardial fibrosis. Echocardiograms revealed that WT mice injected with isoproterenol had lowered ejection fractions and fractional shortening, and increased E´wave deceleration time and E/A ratio compared to their controls. Conversely, Set7 KO mice did not show alteration in these parameters in response to isoproterenol. However, prolonged exposure to isoproterenol induced cardiac dysfunction both in WT and Set7 KO mice. Both isoproterenol and Set7 deletion changed the transcriptional profile of the heart. Moreover, Set7 deletion increased the expression of Pgc1α and mitochondrial DNA content in the heart, and reduced the expression of cellular senescence and inflammation markers in response to isoproterenol. Taken together, our data suggest that Set7 deletion attenuates isoproterenol-induced myocardial fibrosis and delays heart dysfunction, suggesting that Set7 plays an important role in cardiac remodeling and dysfunction in response to stress.

A functional medicine and food homology composition discovery based on disease-related target and data mining against cardiac remodeling

“…Based on the drug-likeness evaluation in Table S3, β-ecdysterone is unable to pass through the blood-brain barrier and cannot directly act on the central nervous system. Since our pathological cardiac remodeling model was established via the method of sympathetic overactivation by ISO 21, 60, 61 , overactivated sympathetic nerves cause dysregulation of the central nervous system and disrupt the balance of activities between sympathetic and parasympathetic nerves 62 . To further explain why the treatment of β-ecdysterone caused alterations in neurotransmitter-related signaling pathways, we designed the following interdisplinary approaches to investigate the crosstalk mechanism of central-peripheral regulation.…”

“…Second, we explored whether β-ecdysterone treatment affects the sympathetic central nervous system. We applied resting-state functional magnetic resonance imaging (rs-fMRI) to achieve real-time and non-invasive detection of whole brain activity [62][63][64] . Animal studies using rs-fMRI are often applied to nervous system diseases.…”