Uric Acid Induces Cardiomyocyte Apoptosis via Activation of Calpain-1 and Endoplasmic Reticulum Stress

Abstract

Background/Aims: Hyperuricemia is associated with an increased risk for multiple cardiovascular diseases, but the underlying mechanisms remain largely elusive. Calpain-1 is a protease that is implicated in several pathological conditions that affect the heart. The aim of this current study was to test the effects of uric acid (UA) on cardiomyocyte survival and cardiac function and to investigate the role of calpain-1 in the UA-induced effects in the heart and their underlying mechanisms. Methods: In vivo, hyperuricemia was induced by oxonic acid (OA) administration in Sprague-Dawley rats for 16 weeks; TUNEL staining was used to identify apoptotic cells. Left ventricular (LV) sections were stained with Sirius Red to evaluate interstitial fibrosis. Cardiac catheterization was performed to evaluate cardiac function. In vitro, cultured H9c2 cells were incubated with different UA concentrations. MTT assays and flow cytometry were used to evaluate cell viability and apoptosis. All related gene expression levels were analyzed by quantitative real-time PCR (qRT-PCR), and all protein expression levels were analyzed by western blotting. Results: Hyperuricemia induction in vivo resulted in cellular apoptosis, interstitial fibrosis and diastolic dysfunction in the rat hearts, as well as increased activation of calpain-1 and endoplasmic reticulum (ER) stress, while allopurinol treatment mitigated the above changes. UA administration in vitro increased apoptosis and decreased H9c2 cell viability in a dose-dependent manner. Increased activation of calpain-1 and ER stress was also observed in the groups with high UA levels. Calpain-1 siRNA and the calpain inhibitor CI-III alleviated UA-induced ER stress and apoptosis, while inhibiting ER stress by tauroursodeoxycholic acid (TUDCA) mitigated UA-induced apoptosis without affecting calpain-1 expression or activity. Conclusions: These findings suggest that UA induces cardiomyocyte apoptosis through activation of calpain-1 and ER stress. These results may provide new insights into the mechanisms of hyperuricemia-associated cardiovascular risks and hopefully identify new treatment targets.

The Key Role of Uric Acid in Oxidative Stress, Inflammation, Fibrosis, Apoptosis, and Immunity in the Pathogenesis of Atrial Fibrillation

“…This could substantially lead to the imbalance of Bax/Bcl-2. In another recent experimental study, Yan et al demonstrated, uric acid induces cardiomyocyte apoptosis via activation of calpain-1 and endoplasmic reticulum stress (ERS) (60). The study extended that Calpain-1 expression was significantly increased after oxonic acid (OA) gavage administration for 16 weeks and p-PERK, GRP78, and CHOP expression was increased in H9c2 cardiomyocytes, suggesting hyperuricemia induced ERS activation.…”

U-Shaped Relationship Between Functional Outcome and Serum Uric Acid in Ischemic Stroke

“…The U shape suggests that SUA may exhibit protective and deleterious effects on stroke outcomes. Previous studies suggested that hyperuricemia was a risk factor for the poor outcomes [30] and through the following pathway: (1) insulin resistance [39]; (2) increasing the risk of hypertension and further aggravated atherosclerosis [40]; (3) impair the selfregulation of the arteriole [41]; (4) UA induces cardiomyocyte apoptosis through activation of calpain-1 and endoplasmic reticulum stress [42]. Furthermore, high UA exposure activated the ROS-AMPK pathway, impaired CD68 expression [43], and induced oxidative damage and inhibited the viability of cardiomyocytes by activating ERK/p38 signaling [44].…”

Uric Acid and Cardiovascular Disease: An Update From Molecular Mechanism to Clinical Perspective

“…UA triggers oxidative stress and endoplasmic reticulum stress to signal the network to induce endothelial dysfunction via activating the protein kinase C (PKC) pathway in human umbilical vein endothelial cells (HUVECs) (Li P. et al, 2016). The latest research also demonstrates that UA can induce cardiomyocyte apoptosis in vitro and in vivo, and its molecular mechanism might be through the activation of calpain-1 and the endoplasmic reticulum stress signaling pathway ( Figure 1B) (Yan et al, 2018). So far, the studies on UA-induced endoplasmic reticulum stress is scarce, but it is certain that there will be more research to clarify the relationship between the two in the future.…”

“…Recent epidemiological studies show that hyperuricemia may be involved in hypertension, diabetes, atherosclerosis, chronic kidney disease, and atrial fibrillation (AF) as well as the occurrence of cardiovascular events (Kuwabara et al, 2017a;Kuwabara et al, 2017b;Kuwabara et al, 2017c;Kuwabara et al, 2018a;Kuwabara et al, 2018b;Maruhashi et al, 2018). Experimental studies show that hyperuricemia promotes the occurrence and development of cardiovascular diseases by regulating molecular signals, such as inflammatory response (Xiao et al, 2015;Johnson et al, 2018;Lu et al, 2019), oxidative stress (Li et al, 2018), insulin resistance (Zhi et al, 2016), endothelial dysfunction (Maruhashi et al, 2018), and endoplasmic reticulum stress (Li P. et al, 2016;Yan et al, 2018).…”