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Klotho attenuates D-galactose-induced cardiac aging through the ROS/NLRP3/pyroptosis pathway
Sui-Sui Wang1, Xu Zhang2, Ze-Zhi Ke3
1Department of Cardiology, First School of Clinical Medicine, The First Affiliated Hospital of Guangdong Pharmaceutical University, 19 Nonglinxia Road, Yuexiu District, Guangzhou 510080, PR China; Department of Nuclear Medicine, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, No.466 Road Xingang, Guangzhou, Guangdong 510317, PR China.
Objective:
Activation of NLRP3 inflammasome contributes to cardiac aging progression. Klotho, a recognised anti-aging protein, exerts protective effects against cardiac aging. In this study, we aimed to elucidate the protective effects of Klotho on D-galactose (D-gal)-induced cardiac aging and the underlying mechanisms.
Methods:
Aging severity in mice was evaluated based on coat condition and serum Klotho levels. Serum levels of interleukin (IL)-1β,lactate dehydrogenase (LDH), superoxide dismutase (SOD), and malondialdehyde were measured to assess cardiac oxidative stress and inflammatory response damage. Cardiac function was evaluated using echocardiography, whereas heart histopathological changes were observed through haematoxylin-eosin (HE) staining, Masson staining, and heart index. Cardiac aging was further assessed with β-galactosidase staining and western blot analysis of aging-related proteins (P53 and P21). Pyroptosis-related protein expression was assessed via western blot, and cardiac tissue reactive oxygen species (ROS) expression levels were determined through dihydroethidium staining. Similar analyses were conducted on D-gal-treated H9C2 cardiomyocytes.
Results:
Compared to wild-type aged mice, Klotho-treated and NLRP3 knockout mice showed markedly reduced back hair loss, elevated serum Klotho and SOD levels, reduced serum IL-1β and LDH, enhanced left ventricular ejection fraction, left ventricular fractional shortening, peak E to peak A ratio, diminished heart size, cardiomyocyte hypertrophy and collagen deposition. Decreased cardiac aging markers, apoptosis-associated speck-like protein (ASC) formation, NLRP3 expression, cleaved-caspase-1, gasdermin D (GSDMD), IL-1β, and IL-18, and lower ROS levels were observed in cardiac tissues. These protective effects were abolished upon Nigericin injection.
Conclusions:
Klotho delays D-gal-induced cardiac aging by regulating the ROS/NLRP3/pyroptosis pathway.
