Abstract
BackgroundCathepsin S (Cat S) is overexpressed in human atherosclerotic and aneurysmal tissues and may contributes to degradation of extracellular matrix, especially elastin, in inflammatory diseases. We aimed to define the role of Cat S in cardiac inflammation and fibrosis induced by angiotensin II (Ang II) in mice.Methods and ResultsCat S-knockout (Cat S−/−) and littermate wild-type (WT) C57BL/6J mice were infused continuously with Ang II (750 ng/kg/min) or saline for 7 days. Cat S−/− mice showed severe cardiac fibrosis, including elevated expression of collagen I and α-smooth muscle actin (α-SMA), as compared with WT mice. Moreover, macrophage infiltration and expression of inflammatory cytokines (tumor necrosis factor α, transforming growth factor β and interleukin 1β) were significantly greater in Cat S−/− than WT hearts. These Ang II-induced effects in Cat S−/− mouse hearts was associated with abnormal accumulation of autophagosomes and reduced clearance of damaged mitochondria, which led to increased levels of reactive oxygen species (ROS) and activation of nuclear factor-kappa B (NF-κB) in macrophages.ConclusionCat S in lysosomes is essential for mitophagy processing in macrophages, deficiency in Cat S can increase damaged mitochondria and elevate ROS levels and NF-κB activity in hypertensive mice, so it regulates cardiac inflammation and fibrosis.
Highlights
Hypertensive heart disease is an inflammatory disease characterized by extensive fibrosis and remodeling of the heart
Cathepsin S (Cat S) in lysosomes is essential for mitophagy processing in macrophages, deficiency in Cat S can increase damaged mitochondria and elevate reactive oxygen species (ROS) levels and nuclear factor-kappa B (NF-kB) activity in hypertensive mice, so it regulates cardiac inflammation and fibrosis
angiotensin II (Ang II) Infusion Increases Cat S Expression in the Heart To determine the role of Cat S in Ang II-induced cardiac fibrosis in vivo, we infused WT and Cat S2/2 mice with a low dose, 750 ng/kg/min, of Ang II for 7 days
Summary
Hypertensive heart disease is an inflammatory disease characterized by extensive fibrosis and remodeling of the heart. Understanding the mechanisms of fibrosis development in the heart during hypertension is pivotal to find new therapies to counteract heart failure. Accumulating evidence suggests that inflammation is a key mechanism contributing to cardiac fibrosis in hypertension and other heart diseases [2]. Myocardial infiltration of pro-inflammatory cells such as activated macrophages is the major event of hypertensive heart failure. These cells release various proinflammatory cytokines, including tumor necrosis factor (TNF)a, interleukin (IL)-1, IL-6 and adhesion molecules [3,4], which stimulates the differentiation of resident cardiac fibroblasts into myofibroblasts and produces excessive extracellular matrix components, leading to cardiac fibrosis [5]. We aimed to define the role of Cat S in cardiac inflammation and fibrosis induced by angiotensin II (Ang II) in mice
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