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Notoginsenoside R1, a unique constituent from the root of Panax notoginseng, exerts anti-inflammatory, anti-oxidative and anti-apoptotic properties. The purpose of this study was to assess the contribution of the anti-inflammatory effects of R1 to the amelioration of isoproterenol (ISO)-induced hypertrophied hearts of atherosclerosis-prone mice. As a model of in vivo atherosclerosis, ApoE-/- C57BL/6 J mice were fed a high-cholesterol diet for 12 weeks. Intraperitoneal injection of R1 (1–50 mg/kg/day) or saline for 7 days was followed by continuous infusion with ISO (25 mg/kg/day) for 14 days to experimentally induce heart hypertrophy. We assessed fibrosis, myocardial function, and protein or mRNA levels of several inflammatory mediators. ISO infusion induced cardiac ventricular contractile and diastolic dysfunction, which was consistent with massive replacement fibrosis and apoptosis in hypertrophied hearts. However, R1 attenuated ISO-induced hypertrophy. R1 suppressed the expression of CC chemokine receptor 2 (CCR2) and prevented Ly6Chigh proinflammatory monocytes and the subsequent myocardial inflammatory responses and expression of various cell-derived factors around the cardiac wound. R1-supressed cardiac dysfunction, atherosclerotic lesions, and inflammatory cytokine accumulation in the myocardium can be partially inhibited by CCR2 translation in bone marrow cells. R1 is a novel cardioprotective agent that can attenuate adverse cardiac dysfunction, hypertrophy, and associated disorders, such as fibrosis. The mechanisms are closely correlated with CCR2, which plays a crucial role in the recruitment of proinflammatory monocytes to sites of inflamed hypertrophic heart tissues.