Abstract
Inflammation has been considered a key component in the pathogenesis and progression of angiotensin II- (Ang II-) induced cardiac hypertrophy and related cardiomyopathy. As a vital mediator of inflammation, the role of the Nlrp3 inflammasome in Ang II-induced cardiomyopathy remains unclear. This study was aimed to determine whether Nlrp3 inflammasome activation and its downstream pathway were involved in Ang II-induced cardiomyopathy. We established an Ang II infusion model in both wild-type and Nlrp3−/− mice to determine the contribution of Nlrp3 to cardiac function. Cardiac fibrosis was determined by Masson's trichrome staining, real-time PCR, and TUNEL assay; cardiac function was assessed by echocardiography. Nlrp3 inflammasome activation and related downstream cytokines were measured by Western blotting and enzyme-linked immunosorbent assays; mitochondrial dysfunction was examined by transmission electron microscopy and real-time PCR. We found that Ang II-infused mice showed impaired cardiac function, as evidenced by increased cardiac fibrosis, apoptosis, inflammation, and left ventricular dysfunction. However, these alterations were significantly alleviated in the mice with Nlrp3 gene deletion. Moreover, Ang II-infused mice showed increased Nlrp3 inflammasome activity relative to that of the cytokines IL-1β and IL-18, increased reactive oxygen species, mitochondrial abnormalities, and decreased mtDNA copy number and ATP synthase activity. These molecular and pathological alterations were also attenuated in Nlrp3 deficient mice. In conclusion, Nlrp3 inflammasome-induced mitochondrial dysfunction is involved in Ang II-induced cardiomyopathy. Nlrp3 gene deletion attenuated mitochondrial abnormalities, cardiac inflammation, oxidative stress, and fibrosis and thus alleviated heart dysfunction and hypertrophy. Targeting the Nlrp3 inflammasome and/or mitochondria may be a therapeutic approach for Ang II-induced cardiac diseases.
Highlights
Cardiovascular disease (CVD) has a high prevalence and has become a major cause of death worldwide [1]
The area of cardiac fibrosis was significantly decreased in the NLRP3-/-/Angiotensin II (Ang II) group
To elucidate the effect of nucleotidebinding domain and leucine-rich repeat-containing PYD-3 (Nlrp3) on angiotensin II- (Ang II-)induced myocardial apoptosis, apoptosis in mouse heart was evaluated by TUNEL staining, and caspase 3 protein expression was analyzed by Western blotting
Summary
Cardiovascular disease (CVD) has a high prevalence and has become a major cause of death worldwide [1]. Cardiac hypertrophy plays a key role in the pathological development of CVD. Excessive intrinsic and extrinsic stimuli, such as inflammation and oxidative stress, can cause cardiac hypertrophy, leading to cardiomyopathy and heart failure [2]. The exact mechanism of cardiac hypertrophy remains unclear. Exploring the underlying pathway may provide new strategies for the prevention and treatment of CVDs. The renin-angiotensin system (RAS) plays an important role in the pathogenesis and progression of cardiomyopathy and other related CVDs. Angiotensin II (Ang II) is widely accepted as a powerful vasoconstrictor and proinflammatory effector and contributes to hypertension and cardiac fibrosis [3]. Sadoshima et al found that Ang II significantly increased
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