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

Physiol Rep. 2019 Apr;7(8):e14071. doi: 10.14814/phy2.14071.


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 Ca2+ handling, caused enhanced sarcoplasmic reticulum (SR) calcium (Ca2+ ) leak, and decreased SR Ca2+ uptake. Furthermore, enhanced ROS production and alteration of Ca2+ 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 Ca2+ handling in the heart.

Keywords: Calcium handling; cardiac hypertrophy; glutaredoxin; heart failure; oxidative stress.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aging / metabolism*
  • Aging / pathology
  • Animals
  • Calcium Signaling
  • Cardiomegaly / genetics*
  • Cardiomegaly / metabolism
  • Cells, Cultured
  • Glutaredoxins / genetics*
  • Glutaredoxins / metabolism
  • Heart Failure / genetics*
  • Heart Failure / metabolism
  • Male
  • Mice
  • Myocytes, Cardiac / metabolism
  • Oxidative Stress
  • Reactive Oxygen Species / metabolism


  • Glutaredoxins
  • Reactive Oxygen Species