Michio Sato1,2, Keishi Miyata1,3, Zhe Tian1, Tsuyoshi Kadomatsu1, Yoshihiro Ujihara4, Jun Morinaga1, Haruki Horiguchi1, Motoyoshi Endo1, Jiabin Zhao1, Shunshun Zhu1, Taichi Sugizaki1, Kimihiro Igata1, Masashi Muramatsu5, Takashi Minami5, Takashi Ito6, Marco E Bianchi7, Satoshi Mohri4, Kimi Araki8,9, Koichi Node2, Yuichi Oike1,8. 1. Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University. 2. Department of Cardiovascular Medicine, Saga University. 3. Department of Immunology, Allergy and Vascular Medicine, Graduate School of Medical Sciences, Kumamoto University. 4. First Department of Physiology, Kawasaki Medical School. 5. Division of Molecular and Vascular Biology, Institute of Resource Development and Analysis, Kumamoto University. 6. Department of Systems Biology in Thromboregulation, Kagoshima University Graduate School of Medical and Dental Science. 7. Chromatin Dynamics Unit, San Raffaele University and Scientific Institute. 8. Center for Metabolic Regulation of Healthy Aging, Graduate School of Medical Sciences, Kumamoto University. 9. Division of Developmental Genetics, Institute of Resource Development and Analysis, Kumamoto University.
Abstract
BACKGROUND: The rapid increase in the number of heart failure (HF) patients in parallel with the increase in the number of older people is receiving attention worldwide. HF not only increases mortality but decreases quality of life, creating medical and social problems. Thus, it is necessary to define molecular mechanisms underlying HF development and progression. HMGB2 is a member of the high-mobility group superfamily characterized as nuclear proteins that bind DNA to stabilize nucleosomes and promote transcription. A recent in vitro study revealed that HMGB2 loss in cardiomyocytes causes hypertrophy and increases HF-associated gene expression. However, it's in vivo function in the heart has not been assessed. Methods and Results: Western blotting analysis revealed increased HMGB2 expression in heart tissues undergoing pressure overload by transverse aorta constriction (TAC) in mice. Hmgb2 homozygous knockout (Hmgb2-/-) mice showed cardiac dysfunction due to AKT inactivation and decreased sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2a activity. Compared to wild-type mice, Hmgb2-/- mice had worsened cardiac dysfunction after TAC surgery, predisposing mice to HF development and progression. CONCLUSIONS: This study demonstrates that upregulation of cardiac HMGB2 is an adaptive response to cardiac stress, and that loss of this response could accelerate cardiac dysfunction, suggesting that HMGB2 plays a cardioprotective role.
BACKGROUND: The rapid increase in the number of heart failure (HF) patients in parallel with the increase in the number of older people is receiving attention worldwide. HF not only increases mortality but decreases quality of life, creating medical and social problems. Thus, it is necessary to define molecular mechanisms underlying HF development and progression. HMGB2 is a member of the high-mobility group superfamily characterized as nuclear proteins that bind DNA to stabilize nucleosomes and promote transcription. A recent in vitro study revealed that HMGB2 loss in cardiomyocytes causes hypertrophy and increases HF-associated gene expression. However, it's in vivo function in the heart has not been assessed. Methods and Results: Western blotting analysis revealed increased HMGB2 expression in heart tissues undergoing pressure overload by transverse aorta constriction (TAC) in mice. Hmgb2 homozygous knockout (Hmgb2-/-) mice showed cardiac dysfunction due to AKT inactivation and decreased sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2a activity. Compared to wild-type mice, Hmgb2-/- mice had worsened cardiac dysfunction after TAC surgery, predisposing mice to HF development and progression. CONCLUSIONS: This study demonstrates that upregulation of cardiac HMGB2 is an adaptive response to cardiac stress, and that loss of this response could accelerate cardiac dysfunction, suggesting that HMGB2 plays a cardioprotective role.
Entities:
Keywords:
Aging; HMGB2; Heart failure; Transverse aorta constriction (TAC) model
Authors: Timo H Lüdtke; Irina Wojahn; Marc-Jens Kleppa; Jasper Schierstaedt; Vincent M Christoffels; Patrick Künzler; Andreas Kispert Journal: Respir Res Date: 2021-03-17