Journal article
RGS6 drives myocyte loss in the diabetic heart via a KLF4/miR-30e/CaMKII-dependent mechanism
Molecular and cellular endocrinology, Vol.622(December 2026), 112895
08/25/2026
DOI: 10.1016/j.mce.2026.112895
PMID: 42633868
Abstract
Heart failure is the leading cause of death in individuals with diabetes mellitus (DM), and no effective treatments exist to treat or prevent hyperglycemia-driven cardiomyopathy. Here, we demonstrate that high glucose triggers regulator of G protein signaling 6 (RGS6) up-regulation in both human and murine cardiomyocytes, the hearts of hyperglycemic mice, and cardiac tissue samples from individuals with heart failure and a history of diabetes. Modulation of RGS6 expression in isolated cardiomyocytes resulted in corresponding changes in the expression of the transcription factor Krüppel-like factor 4 (KLF4), a novel RGS6-interacting protein. Further, RGS6-dependent, KLF4-mediated suppression of microRNA 30e (miR-30e) increased expression of the pro-apoptotic miR-30e target Ca2+/calmodulin-dependent kinase II δ isoform (CaMKIIδ). Importantly, inhibition of either KLF4 or CaMKII or overexpression of miR-30e mitigated the deleterious impact of RGS6 overexpression on myocyte viability. Indeed, cardiac-specific RGS6 knockdown provided marked protection against hyperglycemia-driven oxidative stress, mitochondrial dysfunction, and activation of the intrinsic mitochondrial apoptosis pathway in the murine myocardium. Similarly, inhibition of KLF4 decreased cardiotoxicity resulting from viral overexpression of RGS6 in mouse heart. Thus, RGS6 is both necessary and sufficient to drive cardiac damage resulting from chronic elevations in blood glucose. Together, these data point to RGS6/KLF4 as key sources of pathogenic cardiac damage in individuals with DM.
•High glucose triggers RGS6 up-regulation in both human and murine cardiomyocytes.•KLF4 is a novel RGS6-interacting protein.•RGS6-dependent, KLF4-mediated suppression of microRNA 30e increased expression of CaMKII.•RGS6 is both necessary and sufficient to drive cardiac damage resulting from chronic elevations in blood glucose.
Details
- Title: Subtitle
- RGS6 drives myocyte loss in the diabetic heart via a KLF4/miR-30e/CaMKII-dependent mechanism
- Creators
- Abhishek Singh Sengar - Centre of Biomedical ResearchSreemoyee Chakraborti - Central Forensic Science LaboratoryAnushree Lye - Bose InstituteSumit Kumar Verma - Centre of Biomedical ResearchManish Kumar - Centre of Biomedical ResearchDinesh Kumar - Centre of Biomedical ResearchPranesh Kumar - University of LucknowAdele Stewart - University of IowaBiswanath Maity - Bose Institute
- Resource Type
- Journal article
- Publication Details
- Molecular and cellular endocrinology, Vol.622(December 2026), 112895
- DOI
- 10.1016/j.mce.2026.112895
- PMID
- 42633868
- NLM abbreviation
- Mol Cell Endocrinol
- ISSN
- 0303-7207
- eISSN
- 1872-8057
- Publisher
- Elsevier B.V
- Grant note
- Indian Council of Medical Research: ICMR-EMDR/SG/14/2023-0061 Department of Science of Technology: SERB-CRG/2022/003455
This work was supported by Indian Council of Medical Research (ICMR-EMDR/SG/14/2023-0061) and Department of Science of Technology (SERB-CRG/2022/003455) to BM.
- Language
- English
- Date published
- 08/25/2026
- Academic Unit
- Neuroscience and Pharmacology
- Record Identifier
- 9985220841802771
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