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

Abstract

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.