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.
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