Cathepsin B inhibition attenuates cardiac dysfunction and remodeling following myocardial infarction by inhibiting the NLRP3 pathway

Abstract

Abstract.Recently, cathepsin B has been demonstrated to be involved in myocardial infarction (MI). This study aimed to elucidate the effects of a specific cathepsin B inhibitor, CA-074Me, on cardiac dysfunction, remodeling and fibrosis following MI in a rat model. Furthermore, the potential mechanisms of action of this inhibitor were investigated. In the present study, Sprague-Dawley rats were anesthetized and subjected to a sham operation or left anterior descending coronary artery ligation, followed by intraperitoneal injection of CA-074Me (10 mg/kg/day) or an equal volume of vehicle for 4 weeks. Activation of the cathepsin B and NLRP3 pathway was detected. Cardiac function was assessed by echocardiography, while hypertrophy and fibrosis were determined by Masson's trichrome, immunofluorescence and morphometry. The results demonstrated that cathepsin B-NLRP3 activation was inhibited by CA-074Me treatment. Following such treatment for 4 weeks, the rats demonstrated smaller decreases in cardiac function, and a decrease in cardiomyocyte hypertrophy and the level of fibrosis. Cathepsin B inhibition significantly attenuated cardiac dysfunction, and reduced cardiomyocyte size and cardiac fibrosis in the experimental MI model, by inhibiting NLRP3 activation. This suggested that targeting the cathepsin B-NLRP3 pathway may represent a novel therapeutic strategy to prevent heart failure and remodeling following MI.

Cathepsin B deficiency attenuates cardiac remodeling in response to pressure overload via TNF-α/ASK1/JNK pathway

“…Furthermore, H9c2 cells with increased CTSB expression demonstrated accelerated progression to cardiomyocyte hypertrophy following exposure to an ANG II stimulus, suggesting that CTSB plays a key role in the regulation of hypertrophy in response to pathological stress. Liu et al (17) found that CTSB participates in the regulation of cardiac remodeling in response to myocardial infarction, which is consistent with our study. In the future, it will be important to further define the role of CTSB in the pathophysiological stress conditions in the heart and, most importantly, to determine whether CTSB participates in the regulation of cardiac responses to stress in patients with cardiovascular disease.…”

“…Moreover, increased CTSB expression was reported in H9c2 cardiomyocytes in patients with doxorubicininduced cardiomyopathy (2) and in patients with heart failure secondary to dilated cardiomyopathy (12). More recently, Liu et al (17) found that a specific CTSB inhibitor, CA-074Me, significantly attenuated cardiac remodeling after myocardial infarction. This observation suggested that CTSB plays an important role in cardiovascular disease.…”

The effect of disease on human cardiac protein expression profiles in paired samples from right and left ventricles

“…Cathepsins (cysteine proteases) are implicated in cardiovascular disease and their inhibition is cardioprotective in animal models [26,27] and can degrade unwanted intracellular proteins during ischemic disease [28]. Similarly, the higher level of mitochondrial 60 kDa heat shock protein in left ventricle is cardioprotective against ischemia/reoxygenation [29].…”

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

“…Furthermore, CTSB was associated with an increased risk of cardiovascular events in patients with stable coronary heart disease [18]. A specific CTSB inhibitor, namely CA-074Me, reduced cardiac dysfunction, remodeling, and fibrosis in a rat model of myocardial infarction [181]. Studies aimed to explore the potential of CTS inhibitors for the treatment of cardiovascular diseases are ongoing [19], and targeting CTSs-based therapy might provide new avenues for the treatment of MPSs as well.…”

“…The inhibition of CTSs has been widely explored over the last decades in the field of chronic inflammatory diseases [27,37,204,205], cardiovascular diseases [10,19,181], osteoporosis [70][71][72][73], arthritis [28,206], kidney diseases [30][31][32]84], pancreatitis [207], obesity [208][209][210], cancer [25,34,48,74,82,211], neurodegenerative diseases [39,41,184,185,212,213], and many other pathological states. Multiple inhibitors are currently available, ranging from reversible covalent inhibitors to irreversible inhibitors [214][215][216][217][218] (Table 4).…”