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Research ArticleCardiologyCell biology
Open Access | 
10.1172/jci.insight.190760
1Division of Cardiology, and
2Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
3Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
4Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA.
5State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China.
6Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
7G.V. (Sonny) Montgomery VA Medical Center, Jackson, Mississippi, USA.
Address correspondence to: Zhao V. Wang, 1500 East Duarte Road, Fox North Building, Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, 91010, USA. Phone: 626.218.6565; Email: zhaowang@coh.org.
Authorship note: CL and PZ contributed equally to this work.
Find articles by Li, C. in: PubMed | Google Scholar
1Division of Cardiology, and
2Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
3Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
4Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA.
5State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China.
6Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
7G.V. (Sonny) Montgomery VA Medical Center, Jackson, Mississippi, USA.
Address correspondence to: Zhao V. Wang, 1500 East Duarte Road, Fox North Building, Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, 91010, USA. Phone: 626.218.6565; Email: zhaowang@coh.org.
Authorship note: CL and PZ contributed equally to this work.
Find articles by Zhang, P. in: PubMed | Google Scholar
1Division of Cardiology, and
2Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
3Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
4Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA.
5State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China.
6Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
7G.V. (Sonny) Montgomery VA Medical Center, Jackson, Mississippi, USA.
Address correspondence to: Zhao V. Wang, 1500 East Duarte Road, Fox North Building, Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, 91010, USA. Phone: 626.218.6565; Email: zhaowang@coh.org.
Authorship note: CL and PZ contributed equally to this work.
Find articles by Zhang, K. in: PubMed | Google Scholar
1Division of Cardiology, and
2Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
3Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
4Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA.
5State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China.
6Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
7G.V. (Sonny) Montgomery VA Medical Center, Jackson, Mississippi, USA.
Address correspondence to: Zhao V. Wang, 1500 East Duarte Road, Fox North Building, Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, 91010, USA. Phone: 626.218.6565; Email: zhaowang@coh.org.
Authorship note: CL and PZ contributed equally to this work.
Find articles by Cook, J. in: PubMed | Google Scholar
1Division of Cardiology, and
2Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
3Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
4Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA.
5State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China.
6Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
7G.V. (Sonny) Montgomery VA Medical Center, Jackson, Mississippi, USA.
Address correspondence to: Zhao V. Wang, 1500 East Duarte Road, Fox North Building, Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, 91010, USA. Phone: 626.218.6565; Email: zhaowang@coh.org.
Authorship note: CL and PZ contributed equally to this work.
Find articles by Song, W. in: PubMed | Google Scholar
1Division of Cardiology, and
2Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
3Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
4Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA.
5State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China.
6Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
7G.V. (Sonny) Montgomery VA Medical Center, Jackson, Mississippi, USA.
Address correspondence to: Zhao V. Wang, 1500 East Duarte Road, Fox North Building, Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, 91010, USA. Phone: 626.218.6565; Email: zhaowang@coh.org.
Authorship note: CL and PZ contributed equally to this work.
Find articles by Virostek, M. in: PubMed | Google Scholar
1Division of Cardiology, and
2Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
3Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
4Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA.
5State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China.
6Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
7G.V. (Sonny) Montgomery VA Medical Center, Jackson, Mississippi, USA.
Address correspondence to: Zhao V. Wang, 1500 East Duarte Road, Fox North Building, Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, 91010, USA. Phone: 626.218.6565; Email: zhaowang@coh.org.
Authorship note: CL and PZ contributed equally to this work.
Find articles by Slotabec, L. in: PubMed | Google Scholar
1Division of Cardiology, and
2Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
3Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
4Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA.
5State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China.
6Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
7G.V. (Sonny) Montgomery VA Medical Center, Jackson, Mississippi, USA.
Address correspondence to: Zhao V. Wang, 1500 East Duarte Road, Fox North Building, Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, 91010, USA. Phone: 626.218.6565; Email: zhaowang@coh.org.
Authorship note: CL and PZ contributed equally to this work.
Find articles by Rouhi, N. in: PubMed | Google Scholar
1Division of Cardiology, and
2Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
3Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
4Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA.
5State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China.
6Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
7G.V. (Sonny) Montgomery VA Medical Center, Jackson, Mississippi, USA.
Address correspondence to: Zhao V. Wang, 1500 East Duarte Road, Fox North Building, Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, 91010, USA. Phone: 626.218.6565; Email: zhaowang@coh.org.
Authorship note: CL and PZ contributed equally to this work.
Find articles by Hazari, M. in: PubMed | Google Scholar
1Division of Cardiology, and
2Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
3Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
4Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA.
5State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China.
6Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
7G.V. (Sonny) Montgomery VA Medical Center, Jackson, Mississippi, USA.
Address correspondence to: Zhao V. Wang, 1500 East Duarte Road, Fox North Building, Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, 91010, USA. Phone: 626.218.6565; Email: zhaowang@coh.org.
Authorship note: CL and PZ contributed equally to this work.
Find articles by Adenawoola, M. in: PubMed | Google Scholar
1Division of Cardiology, and
2Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
3Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
4Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA.
5State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China.
6Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
7G.V. (Sonny) Montgomery VA Medical Center, Jackson, Mississippi, USA.
Address correspondence to: Zhao V. Wang, 1500 East Duarte Road, Fox North Building, Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, 91010, USA. Phone: 626.218.6565; Email: zhaowang@coh.org.
Authorship note: CL and PZ contributed equally to this work.
Find articles by Liu, X. in: PubMed | Google Scholar
1Division of Cardiology, and
2Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
3Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
4Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA.
5State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China.
6Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
7G.V. (Sonny) Montgomery VA Medical Center, Jackson, Mississippi, USA.
Address correspondence to: Zhao V. Wang, 1500 East Duarte Road, Fox North Building, Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, 91010, USA. Phone: 626.218.6565; Email: zhaowang@coh.org.
Authorship note: CL and PZ contributed equally to this work.
Find articles by Zhang, H. in: PubMed | Google Scholar
1Division of Cardiology, and
2Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
3Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
4Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA.
5State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China.
6Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
7G.V. (Sonny) Montgomery VA Medical Center, Jackson, Mississippi, USA.
Address correspondence to: Zhao V. Wang, 1500 East Duarte Road, Fox North Building, Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, 91010, USA. Phone: 626.218.6565; Email: zhaowang@coh.org.
Authorship note: CL and PZ contributed equally to this work.
Find articles by Zhang, G. in: PubMed | Google Scholar
1Division of Cardiology, and
2Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
3Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
4Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA.
5State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China.
6Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
7G.V. (Sonny) Montgomery VA Medical Center, Jackson, Mississippi, USA.
Address correspondence to: Zhao V. Wang, 1500 East Duarte Road, Fox North Building, Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, 91010, USA. Phone: 626.218.6565; Email: zhaowang@coh.org.
Authorship note: CL and PZ contributed equally to this work.
Find articles by Niewold, E. in: PubMed | Google Scholar
1Division of Cardiology, and
2Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
3Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
4Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA.
5State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China.
6Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
7G.V. (Sonny) Montgomery VA Medical Center, Jackson, Mississippi, USA.
Address correspondence to: Zhao V. Wang, 1500 East Duarte Road, Fox North Building, Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, 91010, USA. Phone: 626.218.6565; Email: zhaowang@coh.org.
Authorship note: CL and PZ contributed equally to this work.
Find articles by Li, Q. in: PubMed | Google Scholar
1Division of Cardiology, and
2Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
3Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
4Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA.
5State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China.
6Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
7G.V. (Sonny) Montgomery VA Medical Center, Jackson, Mississippi, USA.
Address correspondence to: Zhao V. Wang, 1500 East Duarte Road, Fox North Building, Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, 91010, USA. Phone: 626.218.6565; Email: zhaowang@coh.org.
Authorship note: CL and PZ contributed equally to this work.
Find articles by Fang, Y. in: PubMed | Google Scholar
1Division of Cardiology, and
2Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
3Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
4Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA.
5State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China.
6Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
7G.V. (Sonny) Montgomery VA Medical Center, Jackson, Mississippi, USA.
Address correspondence to: Zhao V. Wang, 1500 East Duarte Road, Fox North Building, Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, 91010, USA. Phone: 626.218.6565; Email: zhaowang@coh.org.
Authorship note: CL and PZ contributed equally to this work.
Find articles by Elhelaly, W. in: PubMed | Google Scholar
1Division of Cardiology, and
2Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
3Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
4Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA.
5State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China.
6Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
7G.V. (Sonny) Montgomery VA Medical Center, Jackson, Mississippi, USA.
Address correspondence to: Zhao V. Wang, 1500 East Duarte Road, Fox North Building, Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, 91010, USA. Phone: 626.218.6565; Email: zhaowang@coh.org.
Authorship note: CL and PZ contributed equally to this work.
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Sun, X.
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1Division of Cardiology, and
2Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
3Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
4Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA.
5State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China.
6Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
7G.V. (Sonny) Montgomery VA Medical Center, Jackson, Mississippi, USA.
Address correspondence to: Zhao V. Wang, 1500 East Duarte Road, Fox North Building, Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, 91010, USA. Phone: 626.218.6565; Email: zhaowang@coh.org.
Authorship note: CL and PZ contributed equally to this work.
Find articles by Guo, X. in: PubMed | Google Scholar
1Division of Cardiology, and
2Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
3Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
4Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA.
5State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China.
6Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
7G.V. (Sonny) Montgomery VA Medical Center, Jackson, Mississippi, USA.
Address correspondence to: Zhao V. Wang, 1500 East Duarte Road, Fox North Building, Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, 91010, USA. Phone: 626.218.6565; Email: zhaowang@coh.org.
Authorship note: CL and PZ contributed equally to this work.
Find articles by Lemoff, A. in: PubMed | Google Scholar
1Division of Cardiology, and
2Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
3Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
4Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA.
5State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China.
6Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
7G.V. (Sonny) Montgomery VA Medical Center, Jackson, Mississippi, USA.
Address correspondence to: Zhao V. Wang, 1500 East Duarte Road, Fox North Building, Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, 91010, USA. Phone: 626.218.6565; Email: zhaowang@coh.org.
Authorship note: CL and PZ contributed equally to this work.
Find articles by Deng, Y. in: PubMed | Google Scholar
1Division of Cardiology, and
2Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
3Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
4Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA.
5State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China.
6Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
7G.V. (Sonny) Montgomery VA Medical Center, Jackson, Mississippi, USA.
Address correspondence to: Zhao V. Wang, 1500 East Duarte Road, Fox North Building, Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, 91010, USA. Phone: 626.218.6565; Email: zhaowang@coh.org.
Authorship note: CL and PZ contributed equally to this work.
Find articles by Gillette, T. in: PubMed | Google Scholar
1Division of Cardiology, and
2Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
3Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
4Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA.
5State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China.
6Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
7G.V. (Sonny) Montgomery VA Medical Center, Jackson, Mississippi, USA.
Address correspondence to: Zhao V. Wang, 1500 East Duarte Road, Fox North Building, Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, 91010, USA. Phone: 626.218.6565; Email: zhaowang@coh.org.
Authorship note: CL and PZ contributed equally to this work.
Find articles by Li, J. in: PubMed | Google Scholar
1Division of Cardiology, and
2Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
3Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
4Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA.
5State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China.
6Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
7G.V. (Sonny) Montgomery VA Medical Center, Jackson, Mississippi, USA.
Address correspondence to: Zhao V. Wang, 1500 East Duarte Road, Fox North Building, Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, 91010, USA. Phone: 626.218.6565; Email: zhaowang@coh.org.
Authorship note: CL and PZ contributed equally to this work.
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Scherer, P.
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1Division of Cardiology, and
2Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
3Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
4Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA.
5State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China.
6Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
7G.V. (Sonny) Montgomery VA Medical Center, Jackson, Mississippi, USA.
Address correspondence to: Zhao V. Wang, 1500 East Duarte Road, Fox North Building, Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, 91010, USA. Phone: 626.218.6565; Email: zhaowang@coh.org.
Authorship note: CL and PZ contributed equally to this work.
Find articles by Wang, Z. in: PubMed | Google Scholar
Authorship note: CL and PZ contributed equally to this work.
Published January 8, 2026 - More info
Published in Volume 11, Issue 4 on February 23, 2026
AbstractCardiomyocyte growth is tightly controlled by multiple signaling pathways. Identification of master kinases in this process is essential in exploring potential targets for the treatment of pathological cardiac hypertrophy and heart failure. Here we identified the mTOR-independent activation of ribosomal protein S6 kinase b1 (Rps6kb1) during cardiomyocyte growth. By utilizing phosphoproteomics in primary neonatal rat ventricular myocytes, we revealed Rps6kb1 as one of most activated kinases under growth stimulation. We further demonstrated the role of Rps6kb1 phosphorylation in pathological cardiac hypertrophy and heart failure. We showed that the phosphorylation of multiple sites in Rps6kb1, including T367 in the kinase domain and S418/T421/S424 in the C-terminal domain, is not directly regulated by the activity of mTOR but coupled with the activation of the MEK1/ERK axis. In mice, cardiomyocyte-specific deletion of Rps6kb1 significantly inhibited both constitutively active ERK– and pressure overload–induced cardiac hypertrophy. In contrast, cardiomyocyte-specific overexpression of wild-type Rps6kb1, rather than the phosphorylation-defective mutant, elevated cardiac hypertrophy and augmented pressure overload–induced heart failure. In conclusion, our findings reveal that the MEK/ERK axis primes Rps6kb1 activation through phosphorylation of 2 separate domains of Rps6kb1, which may play an essential role in cardiac hypertrophy and heart failure under hemodynamic stress.
IntroductionHeart failure is a leading cause of death worldwide (1). Heart-related diseases, including hypertensive heart disease and myocardial infarction, are inevitably associated with the growth of cardiomyocytes, a process also known as cardiac hypertrophy. Under persistent stress, this once adaptive response may decompensate and succumb to heart failure (2). Despite extensive clinical relevance, our understanding of this pathological process remains incomplete (3, 4).
Cardiac hypertrophic growth is a tightly controlled process, in which protein kinases play a pivotal role in relaying cellular signals (5). Among all kinases, mTOR is considered a master regulator that senses divergent environmental cues and controls key cellular processes, including protein synthesis (6). In addition to a fundamental role of mTOR in cardiogenesis (7, 8), genetic disruption of mTOR in adult hearts manifests heightened development of heart failure under pressure overload (9, 10). Nevertheless, the direct downstream targets of mTOR signaling during pathological cardiac remodeling are incompletely understood. Ribosomal protein S6 kinase b1 (Rps6kb1, also known as S6K1), whose phosphorylation at T389 is a hallmark of mTORC1 activity, is probably the most promising candidate, considering its role in protein synthesis (11, 12). However, our understanding of Rps6kb1 in cardiac hypertrophic growth and pathological remodeling remains obscure (13).
Here, through phosphoproteomics analysis in cultured cardiomyocytes, we demonstrate that Rps6kb1 is one of the most prominent kinases during hypertrophic growth. We show that Rps6kb1 is activated by the MEK/ERK axis. We go on to identify 4 residues of Rps6kb1 that are directly phosphorylated by ERK. Furthermore, cardiomyocyte-specific Rps6kb1 deletion in mice almost completely abolished cardiac hypertrophy induced by either ERK activation or pressure overload. Importantly, overexpression of wild-type (WT) Rps6kb1, rather than phosphorylation-defective Rps6kb1, drove cardiac hypertrophic growth. These findings together demonstrate a critical role of the ERK/Rps6kb1 axis in cardiac hypertrophic growth, which may represent a promising target for the treatment of hypertensive heart disease and heart failure.
ResultsmTOR-independent phosphorylation of Rps6kb1 is increased in cardiomyocytes subjected to growth stimulation. To explore the kinase network during cardiomyocyte hypertrophic growth, we employed an unbiased phosphoproteomics approach (Figure 1A). We treated primary neonatal rat ventricular myocytes (NRVMs) with phenylephrine (PE), a commonly used method to model cardiomyocyte hypertrophy in vitro (14). We extracted total proteins and enriched phosphorylated peptides. We then identified the sequences and modifications of peptides by liquid chromatography with tandem mass spectrometry (LC-MS/MS) (Supplemental Tables 1–9; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.190760DS1). Rps6kb1 was one of the most prominent kinases with the highest enrichment when comparing PE with vehicle treatments (Figure 1B), suggesting that Rps6kb1 may play a pivotal role in cardiomyocyte hypertrophic growth.
Figure 1The mTOR-independent phosphorylation of Rps6kb1 in cardiomyocytes under hypertrophic growth. (A) Schematic diagram of phosphoproteomics assay. Neonatal rat ventricular myocytes (NRVMs) were isolated and treated with or without phenylephrine (PE) for 30 minutes. (B) Analysis for all phosphorylated proteins identified in A. Several mTORC1 targets are labeled, including Rps6kb1, Tfeb, Ulk1, Grb10, and 4EBP1. (C) Rapamycin (Rapa) inhibited the phosphorylation of Rps6kb1 at T389 but not the T421/S424 sites. NRVMs were stimulated by PE for 15 minutes with or without cotreatment with Rapa. Note that PE and Rapa were simultaneously added into culture medium. (D) Quantification of the results in C. n = 3. NS, not significant. Two-way ANOVA was conducted, followed by Tukey’s multiple-comparison test for D. Data are presented as mean ± SEM.
Rps6kb1 is an established downstream kinase of mTOR complex 1 (mTORC1), a master regulator of cell growth (6). In addition to mTORC1, Rps6kb1 is also phosphorylated by other kinases under different physiological or pathophysiological conditions (15). Nevertheless, the role of Rps6kb1 and its activating kinase(s) remain to be fully illustrated in cardiac hypertrophy. In addition to Rps6kb1, mTORC1 also directly phosphorylates other targets, such as 4EBP1, Ulk1, Tfeb, and Grb10. Importantly, we found that the enrichment of these targets of mTORC1 was less than that for Rps6kb1 (Figure 1B), indicating that mTORC1 activity may not fully account for the drastic elevation of Rps6kb1 phosphorylation under cardiomyocyte growth stimulation.
To further evaluate the change in Rps6kb1 phosphorylation after PE treatment, we employed 2 antibodies, one recognizing the mTORC1-dependent phosphorylation at T389 and the other one for the phosphorylation of T421 and S424 sites in the C-terminal domain (CTD) of Rps6kb1 whose upstream kinase remains unidentified. We found that the phosphorylation of T421/S424 was significantly increased upon PE treatment, as well as the mTOR-dependent phosphorylation of T389 (Figure 1, C and D). Consistent with the phosphoproteomics results, phosphorylation of 4EBP1 was not increased, indicating moderate activation of mTORC1. Importantly, simultaneous rapamycin treatment with PE completely abolished the induction of T389 phosphorylation of Rps6kb1 but had minimal effect on T421/S424 phosphorylation (Figure 1, C and D). Moreover, the activity of Rps6kb1 in NRVMs, manifested by the phosphorylation of S6, was activated regardless of rapamycin treatment. These findings prompted us to hypothesize that an unrecognized upstream kinase, independent from mTORC1, may phosphorylate and activate Rps6kb1 during cardiomyocyte hypertrophic growth.
Activation of the MEK/ERK axis is coupled with Rps6kb1 phosphorylation. We next sought to identify the kinase that is responsible for the mTOR-independent phosphorylation of Rps6kb1. In the phosphoproteomics data, we extracted phosphorylated peptides and identified a total of 8,639 sites, among which 1,383 sites were never reported (Supplemental Figure 1, A and B). We then performed motif enrichment analysis for peptides that had significant differences between vehicle and PE groups. We identified 5 motifs with statistical significance (Figure 2A and Supplemental Figure 1C). We then predicted potential kinases for these motifs. Importantly, ERK showed the most abundant phosphorylation targets under PE treatment in cardiomyocytes (Figure 2A). Next, a phospho-kinase array assay was conducted comparing PE to vehicle treatments. Phosphorylation of ERK1/2 was also increased in cardiomyocytes (Figure 2B). We further examined the effect of various kinase inhibitors on the phosphorylation of Rps6kb1 at T421/S424 (
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