Nlrp3 Deficiency Alleviates Angiotensin II‐Induced Cardiomyopathy by Inhibiting Mitochondrial Dysfunction

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.

Inhibition of cGAS in Paraventricular Nucleus Attenuates Hypertensive Heart Injury Via Regulating Microglial Autophagy

“…M-mode images were acquired with a Vevo 3100 high-frequency ultrasound system (VisualSonics, Toronto, ON, Canada) and a 30-MHz imaging transducer. The echocardiographic parameters measured were left ventricular ejection fraction, left ventricular fractional shortening, left ventricular end-systolic volume, left ventricular end-diastolic volume, left ventricular internal dimension-systole, and left ventricular internal dimension-diastole [ 33 , 34 ]. For the low heart rate which was associated with low cardiac function during the anesthesia, when the heart rate of mice was founded lower than 200 per minute during the anesthesia, the final monitoring of functional index would be stopped and the mice would be sacrificed for subsequent histological observation.…”

Mitochondria in Pathological Cardiac Hypertrophy Research and Therapy

“…In addition to mitochondrial morphological alterations, cardiac hypertrophy also led to mitochondrial dysfunction, which was accompanied by insufficient mitochondrial biogenesis, damaged mtDNA, disordered intracellular ATP synthesis, and low levels of TFAM and PGC1a. Surprisingly, Nlrp3 depletion remarkably reversed the decreased expression of PGC1a and TFAM, abnormal mtDNA and ATP synthase in the hypertrophic heart caused by Ang II infusion ( 68 ). Polycystic kidney disease 2-like 1 (PKD2L1), known to serve as an important sour sensor in taste cells, played possible roles in cardiac hypertrophy.…”

Structure and Function of Mitochondria‐Associated Endoplasmic Reticulum Membranes (MAMs) and Their Role in Cardiovascular Diseases

“…As a cytosolic multiprotein complex, the inflammasome is responsible for the activation of inflammatory responses. The NLRP3 complex is currently the only known MAMrelated inflammasome complex [133]. A wide variety of stimuli can be used to activate NLRP3.…”