LMOD2 attenuates Ang II-induced cardiomyocyte hypertrophy by activating the Nrf2-mediated antioxidant pathway

Pathological cardiac hypertrophy constitutes a common pathway in heart failure progression. Although previous studies have identified LMOD2 as a protective factor against dilated cardiomyopathy, its functional role and mechanistic involvement in pathological hypertrophy remain elusive. Here our study demonstrates that LMOD2 expression is significantly downregulated in angiotensin II (Ang II)-induced H9c2 cardiomyocyte hypertrophy. Further studies revealed that LMOD2 overexpression markedly attenuates cardiomyocyte enlargement and decreases expression of hypertrophic markers including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and myosin heavy chain 7 (MYH7), whereas siRNA-mediated silencing exacerbates these pathological changes. Mechanistically, LMOD2 suppresses oxidative stress by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant signaling pathway, evidenced by upregulation of Nrf2, solute carrier family 7 member 11 (SLC7A11), heme oxygenase-1 (HO-1), and glutathione peroxidase 4 (GPX4), alongside reduced levels of reactive oxygen species (ROS), malondialdehyde (MDA), and 4-hydroxy-2-nonenal (4-HNE) and elevated glutathione (GSH) content. Notably, nucleocytoplasmic fractionation assays revealed that LMOD2 overexpression promoted Nrf2 nuclear accumulation, whereas LMOD2 silencing attenuated Nrf2 translocation into the nucleus. Pharmacological rescue experiments further demonstrated that the Nrf2 inhibitor ML385 abolished the protective effects of LMOD2 overexpression, while the Nrf2 activator sulforaphane (SFN) partially reversed the aggravated hypertrophic phenotype induced by LMOD2 deficiency, confirming that the anti-hypertrophic action of LMOD2 is causally dependent on the functional integrity of the Nrf2 pathway. Our results reveal that LMOD2 functions as a crucial suppressor of Ang II-induced cardiomyocyte hypertrophy by orchestrating Nrf2-mediated antioxidant defenses, thereby revealing a potential therapeutic target for preventing pathological cardiac remodeling.