Cardiac‐specific ablation of glutaredoxin 3 leads to cardiac hypertrophy and heart failure

Abstract

Growing evidence suggests that redox‐sensitive proteins including glutaredoxins (Grxs) can protect cardiac muscle cells from oxidative stress‐induced damage. Mammalian Grx3 has been shown to be critical in regulating cellular redox states. However, how Grx3 affects cardiac function by modulating reactive oxygen species ( ROS ) signaling remains unknown. In this study, we found that the expression of Grx3 in the heart is decreased during aging. To assess the physiological role of Grx3 in the heart, we generated mice in which Grx3 was conditionally deleted in cardiomyocytes (Grx3 conditional knockout ( CKO ) mice). Grx3 CKO mice were viable and grew indistinguishably from their littermates at young age. No difference in cardiac function was found comparing Grx3 CKO mice and littermate controls at this age. However, by the age of 12 months, Grx3 CKO mice exhibited left ventricular hypertrophy with a significant decrease in ejection fraction and fractional shortening along with a significant increase of ROS production in cardiomyocytes compared to controls. Deletion of Grx3 also impaired Ca 2+ handling, caused enhanced sarcoplasmic reticulum ( SR ) calcium (Ca 2+ ) leak, and decreased SR Ca 2+ uptake. Furthermore, enhanced ROS production and alteration of Ca 2+ handling in cardiomyocytes occurred, prior to cardiac dysfunction in young mice. Therefore, our findings demonstrate that Grx3 is an important factor in regulating cardiac hypertrophy and heart failure by modulating both cellular redox homeostasis and Ca 2+ handling in the heart.

Large-scale sequencing of flatfish genomes provides insights into the polyphyletic origin of their specialized body plan

“…Among them, cardiovascular adaptation is a surprising association with rapid sequence evolution during transition from the water column to benthic colonization. Our results revealed that this process may involve not only a cardiac morphological reorganization resulting from selective pressure on cardiac morphogenesis genes ( popdc2 and irx4a ) 54 , 56 , but also cardiac functional remodeling resulting from selective pressure on genes associated with cardiac conducting efficiency ( tmem43 and popdc2 ) 52 , 54 and antioxidant capacities ( glrx1 and glrx3 ) 55 , 57 (Extended Data Fig. 3 , Supplementary Tables 90 – 97 and Supplementary Notes 20 , 21 and 23 ).…”

“… 56 ) and glrx 3 (ref. 57 ) in FLP) (Supplementary Tables 90 – 97 , Extended Data Fig. 3 and Supplementary Notes 20 and 21 ), possibly suggesting a similar remodeling of their visual, immune, respiratory and circulatory systems in benthic adaptation to seafloor colonization (Extended Data Fig.…”

Role of Glutaredoxin-1 and Glutathionylation in Cardiovascular Diseases

“…In addition to Glrx, Glrx2 and Glrx3 have also been shown to play a role in cardiac hypertrophy. Deletion of Glrx2 in mice hearts results in cardiac hypertrophy and fibrosis as well as hypertension [61], while Glrx3 KO in mice results in cardiac hypertrophy and heart failure [63]. Glrx3 KO mice were found to have significant left ventricular hypertrophy compared to their WT counterparts at 12 months of age.…”

Crucial Role of Mammalian Glutaredoxin 3 in Cardiac Energy Metabolism in Diet-induced Obese Mice Revealed by Transcriptome Analysis

“…Differential expression was observed in the developing mammary glands [14] and also in muscle cells following hydrogen peroxide treatment [8]. As regards to the current investigation, Grx3 expression was also found to decline in the heart during aging [12]. Here we wanted to determine the impact of HFD feeding on Grx3 expression in the heart.…”