MBNL1 Modulates Nek7 to Facilitate Pathological Cardiac Hypertrophy via NLRP3

Hypertension-induced cardiac hypertrophy constitutes the principal cause of heart failure, malignant arrhythmias, and sudden cardiac death. Nek7 (NIMA-Related Kinase 7), a member of the serine/threonine kinase family, is a multifunctional protein kinase that plays a crucial role in regulating the cell cycle, mitosis, and inflammation, but its role in cardiac hypertrophy remains unclear.

We subjected AAV9-cTnT-si-Nek7 mice to pressure overload by means of transverse aortic constriction and evaluated cardiac function, cardiac hypertrophy, and inflammasome activation. In neonatal mouse cardiomyocytes treated with Ang (angiotensin) II, the effects of si-Nek7 (small interfering RNA targeting Nek7) or NLRP3 (NLR Family, Pyrin Domain-Containing 3 Protein) inhibition on cardiomyocyte hypertrophy were examined. The effect of Nek7 in regulating cardiac hypertrophy was examined by administering si-MBNL1 (muscleblind-like splicing regulator 1) through tail vein knockdown in transverse aortic constriction treated mice.

Nek7 expression was significantly upregulated in both transverse aortic constriction induced cardiac hypertrophy models in vivo and Ang II-stimulated neonatal mouse cardiomyocytes in vitro. Knockdown of Nek7 attenuated Ang II-induced cardiomyocyte hypertrophy and inhibited the activation of the NLRP3 inflammasome. Knockdown of Nek7 with AAV9-si-Nek7 significantly improved cardiac function and reduced hypertrophy in transverse aortic constriction mice. Conversely, Nek7 overexpression exacerbated hypertrophy and promoted NLRP3 inflammasome assembly, leading to pyroptosis via ROS (reactive oxygen species)-dependent pathways. Mechanistically, Nek7 directly bound to NLRP3, and its prohypertrophic effects were abrogated by NLRP3 inhibition. Additionally, MBNL1, as an RNA-binding protein, binds to Nek7 mRNA, thereby regulating Nek7 transcription and further affecting its expression level. MBNL1 was identified as an upstream regulator of Nek7, with knockdown of MBNL1 suppressing Nek7 expression and alleviating cardiac hypertrophy in vivo.

Nek7 drives pathological cardiac hypertrophy by activating the NLRP3 inflammasome and promoting cardiomyocyte pyroptosis, with MBNL1 acting as an upstream regulator. Targeting the MBNL1-Nek7-NLRP3 axis may offer a novel therapeutic strategy for preventing cardiac hypertrophy and heart failure.