Abstract
Cardiovascular disease is expected to remain the leading cause of death worldwide despite the introduction of proprotein convertase subtilisin/kexin type 9 inhibitors that effectively control cholesterol. Identifying residual risk factors for cardiovascular disease remains an important step for preventing and clinically managing the disease. Here we report cardiac injury and increased mortality occurring despite a 50% reduction in plasma cholesterol in a mouse model of phytosterolemia, a disease characterized by elevated levels of dietary plant sterols in the blood. Our studies show accumulation of stigmasterol, one of phytosterol species, leads to left ventricle dysfunction, cardiac interstitial fibrosis and macrophage infiltration without atherosclerosis, and increased mortality. A pharmacological inhibitor of sterol absorption prevents cardiac fibrogenesis. We propose that the pathological mechanism linking clinical sitosterolemia to the cardiovascular outcomes primarily involves phytosterols-induced cardiac fibrosis rather than cholesterol-driven atherosclerosis. Our studies suggest stigmasterol is a potent and independent risk factor for cardiovascular disease.
Highlights
Cardiovascular disease is expected to remain the leading cause of death worldwide despite the introduction of proprotein convertase subtilisin/kexin type 9 inhibitors that effectively control cholesterol
To dissect confounding factors associated with clinical sitosterolemia and assess the impact of β-sitosterol, campesterol, stigmasterol and cholesterol to cardiovascular endpoints, we developed a mouse model of phytosterolemia using C57BL/6 mice with Abcg[5] and Abcg[8] double knockout (DKO) to compare with C57BL/6 wildtype (WT) mice[36]
Reductions of plasma cholesterol in DKO cohorts fed chow and phytosterols-rich diet (PSRD) were corroborated by reductions of hepatic mRNA expression of HMG-CoA reductase (Hmgcr), the ratelimiting enzyme for de novo cholesterol synthesis (Fig. 1b)
Summary
Cardiovascular disease is expected to remain the leading cause of death worldwide despite the introduction of proprotein convertase subtilisin/kexin type 9 inhibitors that effectively control cholesterol. We report cardiac injury and increased mortality occurring despite a 50% reduction in plasma cholesterol in a mouse model of phytosterolemia, a disease characterized by elevated levels of dietary plant sterols in the blood. Phytosterolemic patients often manifest fatal myocardial infarction and sudden cardiac death at a young age[9,10,11] This disorder is characterized by elevated plasma concentrations of phytosterols including β-sitosterol, campesterol, and stigmasterol[9,12]. Presence of heterogeneous genetic backgrounds with other spontaneous mutations may contribute to cardiovascular phenotype[29,30,31] It remains unclear whether cardiovascular events observed in phytosterolemic patients are a direct result of vascular atherosclerosis or primarily a cardiac focused lesion. We dissect the confounding factors pertaining to phytosterolemia and elucidate a pathophysiological mechanism that links stigmasterol to cardiovascular disease
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