Regulator of G-protein signaling 10 (RGS10) is an important member of the RGS family and produces biological effects in multiple organs.We used a genetic approach to study the role of RGS10 in the regulation of pathological cardiac hypertrophy and found that RGS10 can negatively influence pressure overload-induced cardiac remodeling.RGS10 expression was markedly decreased in failing human hearts and hypertrophic murine hearts.The extent of aortic banding (AB)-induced cardiac hypertrophy,dysfunction and fibrosis in RGS10-knockout mice was exacerbated, whereas the heart of transgenic mice with cardiac-specific RGS10 overexpression exhibited an alleviated response to pressure overload.Consistently, RGS10 also inhibited an angiotensin Ⅱ (Ang Ⅱ)-induced hypertrophic response in isolated cardiomyocytes.Mechanistically, cardiac remodeling improvement elicited by RGS10 was associated with the abrogation of mitogen-activated-protein kinase kinase (MEK) 1/2-extracellular signal-regulated protein kinase 1/2 (ERK1/2) signaling.Furthermore, the inhibition of MEK-ERK1/2 transduction abolished RGS10 deletion-induced hypertrophic aggravation.These findings place RGS10 and its downstream signaling MEK-ERK1/2 as crucial regulators of pathological cardiac hypertrophy following pressure overload and identify this pathway as a potential therapeutic target to attenuate the pressure overload-driven cardiac remodeling.