Apolipoprotein A-I proteolysis in aortic valve stenosis: role of cathepsin S

Abstract

Aortic valve stenosis (AVS) is the most common valvular heart disease in the Western world. Therapy based on apolipoprotein A-I (apoA-I), the major protein component of high-density lipoproteins, results in AVS regression in experimental models. Nevertheless, apoA-I degradation by proteases might lead to suboptimal efficacy of such therapy. An activatable probe using a quenched fluorescently labeled full-length apoA-I protein was generated to assess apoA-I-degrading protease activity in plasma derived from 44 men and 20 women with severe AVS (age 65.0 ± 10.4 years) as well as from a rabbit model of AVS. In human and rabbit AVS plasma, apoA-I-degrading protease activity was significantly higher than in controls (humans: 0.038 ± 0.009 vs 0.022 ± 0.005 RFU/s, p < 0.0001; rabbits: 0.033 ± 0.016 vs 0.017 ± 0.005 RFU/s, p = 0.041). Through the use of protease inhibitors, we identified metalloproteinases (MMP) as exerting the most potent proteolytic effect on apoA-I in AVS rabbits (67%, p < 0.05 vs control), while the cysteine protease cathepsin S accounted for 54.2% of apoA-I degradation in human plasma (p < 0.05 vs control) with the maximum effect seen in women (68.8%, p < 0.05 vs men). Accordingly, cathepsin S activity correlated significantly with mean transaortic pressure gradient in women (r = 0.5, p = 0.04) but not in men (r = - 0.09, p = 0.60), and was a significant independent predictor of disease severity in women (standardized beta coefficient 0.832, p < 0.001) when tested in a linear regression analysis. ApoA-I proteolysis is increased in AVS. Targeting circulating cathepsin S may lead to new therapies for human aortic valve disease.

RETRACTED: Mammalian STE20-Like Kinase 2 Promotes Lipopolysaccharides-Mediated Cardiomyocyte Inflammation and Apoptosis by Enhancing Mitochondrial Fission

“…Myocardial inflammation is the hallmark of several cardiovascular disorders, such as myocardial infarction, myocardial ischemia-reperfusion injury, diabetic cardiomyopathy, and sepsis-related myocardial damage (Gebhard et al, 2018;Zhong et al, 2019). The immune cells and pro-inflammatory cytokines involved in the inflammatory process promote cardiomyocyte dysfunction, which contributes to cardiovascular disease progression, severity, and outcomes (Ziegler, 2005).…”

Irisin activates Opa1-induced mitophagy to protect cardiomyocytes against apoptosis following myocardial infarction

“…Equal quantities of total protein were separated by 10% SDS-PAGE and transferred to nitrocellulose membranes (Millipore, Bedford, MA, USA). The membranes were incubated with primary antibodies at 4°C for 15 hours [106]. Following the incubation, the membranes were incubated with the respective secondary antibodies at 25°C for 90 minutes.…”

Pathological Roles of Mitochondrial Oxidative Stress and Mitochondrial Dynamics in Cardiac Microvascular Ischemia/Reperfusion Injury

“…In response to stress, reactive oxygen species (ROS) are produced by mitochondria and employed as a second messenger to transduce extracellular signal [38,39]. Mitochondrial fusion [40] and fission [41,42], together with mitophagy (removal of defected mitochondria), are also involved in the regulation of cell homeostasis through affecting the mitochondrial quality control [43,44]. Here, we summarize and discuss the main regulatory aspects of mitochondrial oxidative stress and mitochondrial dynamics in cardiac microvascular I/R injury ( Figure 1).…”