Protections of transcription factor BACH2 and natural product myricetin against pathological cardiac hypertrophy and dysfunction

Abstract

Pathological hypertrophic myocardium under consistent adverse stimuli eventually can cause heart failure. This study aims to explore the role of BACH2, a member of the basic region leucine zipper transcription factor family, in cardiac hypertrophy and failure. Transverse aortic constriction surgery was operated to induce cardiac hypertrophy and failure in mice. BACH2 was overexpressed in mice through tail vein injection of AAV9-Bach2. Mice with systemic or cardiac-specific knockdown of Bach2 were adopted. Neonatal rat ventricular myocytes (NRVMs) were isolated and infected with lentivirus to overexpress Bach2 or transfected with siRNA to knock down Bach2. Our data showed that overexpression of BACH2 ameliorated TAC-induced cardiac hypertrophy and failure in mice and decreased isoproterenol (ISO)-triggered myocyte hypertrophy in NRVMs. Systemic or cardiac-specific knockdown of Bach2 worsened the cardiac hypertrophy and failure phenotype in mice. Further assays showed that BACH2 bound to the promotor region of Akap6 at the -600 to -587 site and repressed its expression, which functioned as a crucial scaffold for cardiac hypertrophy and failure signaling pathways. Small molecular natural product library screening suggested that myricetin could up-regulate expression of Bach2 and simultaneously suppress the transcriptional levels of hypertrophic marker genes Bnp and Myh7. Further studies showed that myricetin exerted a BACH2-dependent protective effect against cardiac hypertrophy in vivo and in vitro. Taken together, our findings demonstrated that BACH2 plays a crucial role in the regulation of cardiac hypertrophy and failure and can be a potential therapeutic target in the future.

Increased Secreted Frizzled-Related Protein 2 in Hypertension-Induced Left Ventricular Remodeling

“…The transverse aortic constriction (TAC) procedure was the same as in our previous study [ 17 ]. After surgery, mice were treated with intragastric myricetin (200 mg/kg/day) or vehicle for 4 weeks.…”

“…Myricetin is a plant-derived flavonoid with cardioprotective effects [ 14 , 15 , 16 ]. Our previous study, alongside others, found that myricetin can ameliorate pressure overload-induced LVH through the BTB domain and CNC homolog 2 (BACH2)/A-kinase anchoring protein 6 (AKAP6) pathway [ 17 ] or NFE2-like bZIP transcription factor 2 (Nrf2) and JUN N-terminal kinase 1/2 (JNK1/2) signaling pathway [ 18 ]. Moreover, chronic administration of myricetin ameliorated hypertension in different animal models [ 19 , 20 ].…”

Mitophagy and Traumatic Brain Injury: Regulatory Mechanisms and Therapeutic Potentials

“…As discussed previously, TBI originates from primary injuries, most commonly induced by external injuries, and then gradually evolves into secondary damage, accompanied with inflammatory responses, oxidative stress, and cell death [87]. During TBI progression, these biological processes cooperate with mitophagy to maintain proper mitochondrial quality, which determines the fate neurons.…”

Strophioblachins A–K, Structurally Intriguing Diterpenoids fromStrophioblachia fimbricalyxwith Potential Anticardiac Hypertrophic Inhibitory Activity

“…There is growing evidence that inhibiting cardiac hypertrophy helps prevent its transition to heart failure. , The present clinical management of cardiac hypertrophy is still difficult because there are no efficient medications. Many natural compounds derived from plants have been investigated for their effects on cardiac hypertrophy in recent years. , Diterpenoids, in particular, offer therapeutic potential for reducing ventricular hypertrophy. − …”