Cardiac aging is characterized by myocardial hypertrophy, fibrosis, and diastolic dysfunction. Human kallikrein (hKLK1) protects against fibrosis in various pathogenic states. However, the effects of hKLK1 overexpression on cardiac aging-related fibrosis and the underlying mechanisms remain unknown. Moreover, the role of hKLK1 in regulating macrophage function leading to cardiac fibrosis has not been investigated. Thus, in this study, we determined the effects of hKLK1 on cardiac aging and explored the mechanisms through which hKLK1 regulated aging-related fibrosis. Echocardiographic measurements showed that aging caused significant alternations in cardiac morphology, hypertrophy, and fibrosis in rats, and hKLK1 overexpression protected against aging-induced cardiac dysfunction. Compared with wild-type hearts, the hKLK1 transgene decreased the expression of monocyte chemoattractant protein 1 and suppressed mitochondrial dysfunction and excess oxidative stress, leading to decreased recruitment and retention of alternatively activated (M2) macrophages and reduced secretion of profibrotic cytokines mediated by the TGF-β1-Smad3 signaling pathway in hearts of aging rats. Furthermore, these cardioprotective effects of hKLK1 overexpression were associated with the Janus kinase-signal transducer and activator of transcription 3 signaling pathway. H2O2-induced senescence promoted the differentiation of RAW264.7 cells into M2-type cells induced by IL-4 treatment. Bradykinin treatment relieved the migratory capacity of macrophages induced by H2O2. Thus, hKLK1 overexpression reduced cardiac fibrosis and improved aging-related cardiac dysfunction through reduced shift of macrophages to M2 macrophages, indicating that hKLK1 may alleviate aging-related cardiac dysfunction.-Hu, D., Dong, R., Yang, Y., Chen, Z., Tang, Y., Fu, M., Wang, D. W., Xu, X., Tu, L. Human kallikrein overexpression alleviates cardiac aging by alternatively regulating macrophage polarization in aged rats.
Keywords: cardiac fibrosis; mitochondria dysfunction; oxidative stress.