The Akt pathway mediates the protective effects of myeloid differentiation protein 1 in pathological cardiac remodelling.

aimsMyeloid differentiation protein 1 (MD1) was shown to ameliorate pressure overload-induced cardiac hypertrophy and fibrosis by negatively regulating the MEK-ERK1/2 and NF-κB pathways. However, whether MD1 modulates cardiac function and whether the Akt pathway mediates the benefits of MD1 in pressure overload-induced cardiac remodelling remain unclear. METHODS AND

resultsMale cardiac-specific transgenic MD1 (MD1-TG) mice, MD1-knockout (KO) mice and wild-type (WT) littermates aged 8-10 weeks were subjected to sham operation and aortic banding (AB) for 4 weeks. Then, left ventricular (LV) hypertrophy, fibrosis and function of the mice were assessed. When compared with WT-AB mice, MD1-TGs showed decreased cross-sectional area (CSA) of cardiomyocytes (P < 0.001), mRNA expression of β-myosin heavy chain (β-MHC) (P < 0.02), ratios of heart weight/body weight and heart weight/tibia length (P < 0.04) and collagen volume fraction (P < 0.001). The LV end-diastolic diameter was reduced, and LV ejection fraction and fractional shortening were improved in MD1-TG-AB mice than in WT-AB mice (P < 0.05). In cultured H9C2 cells, adenovirus vector-mediated MD1 overexpression decreased angiotensin II-induced mRNA expression of brain natriuretic peptide (BNP) and β-MHC and cell CSA (P < 0.002), whereas knockdown of MD1 by shRNA exhibited opposite effects (P < 0.04). Mechanistically, MD1 suppressed pathological cardiac remodelling at least partly by blocking Akt pathway. Akt inactivation by MK2206 largely offset the pro-hypertrophic effects of MD1 deficiency in angiotensin II-stimulated cardiomyocytes.

conclusionsThe Akt pathway mediates the protective effects of MD1 in pressure overload-induced cardiac remodelling in mice. Targeting MD1 may provide therapeutic strategy for the treatment of pathological cardiac remodelling and heart failure.