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Calmodulin kinase II inhibition protects against structural heart disease

Abstract

β-Adrenergic receptor (βAR) stimulation increases cytosolic Ca2+ to physiologically augment cardiac contraction, whereas excessive βAR activation causes adverse cardiac remodeling, including myocardial hypertrophy, dilation and dysfunction, in individuals with myocardial infarction. The Ca2+-calmodulin–dependent protein kinase II (CaMKII) is a recently identified downstream element of the βAR-initiated signaling cascade that is linked to pathological myocardial remodeling and to regulation of key proteins involved in cardiac excitation-contraction coupling. We developed a genetic mouse model of cardiac CaMKII inhibition to test the role of CaMKII in βAR signaling in vivo. Here we show CaMKII inhibition substantially prevented maladaptive remodeling from excessive βAR stimulation and myocardial infarction, and induced balanced changes in excitation-contraction coupling that preserved baseline and βAR-stimulated physiological increases in cardiac function. These findings mark CaMKII as a determinant of clinically important heart disease phenotypes, and suggest CaMKII inhibition can be a highly selective approach for targeting adverse myocardial remodeling linked to βAR signaling.

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Figure 1: A genetic model of cardiac CaMKII inhibition.
Figure 2: CaMKII inhibition improves adverse ventricular remodeling after myocardial infarction.
Figure 3: CaMKII inhibition protects cellular mechanical function and preserves [Ca2+]i homeostasis after myocardial infarction.
Figure 4: CaMKII is a downstream element in the βAR signaling cascade.
Figure 5: Cellular mechanical responses to βAR stimulation are preserved during CaMKII inhibition.
Figure 6: The effects of CaMKII inhibition on ICa.

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Acknowledgements

We acknowledge support from the US National Institutes of Health (HL070250 and HL046681 to M.E.A., MH63232 to R.J.C., EY11500 and GM63097 to G.S. and HL25675, HL36974, HL70709, HL67849 to W.J.L.) and a US National Institutes of Health training grant (HL70511) for C.E.G., and an American Heart Association postdoctoral fellowship (M.S.C.K.). Mark E. Anderson is an Established Investigator of the American Heart Association. J. Yang, M. Bass, Y. Hou, L. Gleaves, C. Perlroth and R. Towne provided technical assistance. J. Robbins provided the αMHC cDNA for creating the transgenic mice. J. Corbin, A. George, J.T. Kimbrough, D.E. Vaughan and D.M. Roden provided criticisms. Echocardiograms and surgery were performed in the Vanderbilt Mouse Metabolic Core Facility and transgenic mice were engineered in the Vanderbilt Mouse Transgenic Core Facility, both supported by the US National Institutes of Health.

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Correspondence to Mark E Anderson.

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Competing interests

Mark Anderson is a named incentor on a patent for using calmodulin kinase II inhibitors to treat arrhythmias. He is also a named inventor on a patent application to use calmodulin kinase II inhibition as a therapy for structural heart disease.

Supplementary information

Supplementary Fig. 1

Similar heart weights (wt) and left ventricular (LV) chamber dimensions in AC3-I(I), wild type (WT) and AC3-C (C) hearts. (PDF 51 kb)

Supplementary Fig. 2

Similar protein phosphatase expression in AC3-I, WT and AC3-C hearts. (PDF 93 kb)

Supplementary Fig. 3

Quantification of surgical myocardial infarctions. (PDF 43 kb)

Supplementary Fig. 4

Quantification of interventricular septal thickness after myocardial infarction surgery. (PDF 85 kb)

Supplementary Fig. 5

Heart rates in wild type mice 24 hours after injection with KN-93 or KN-92, at baseline or up to three weeks after myocardial infarction. (PDF 126 kb)

Supplementary Fig. 6

Excitation-contraction coupling protein expression in AC3-I, AC3-C and wild type hearts. (PDF 147 kb)

Supplementary Fig. 7

Ryanodine receptor Ca2+ spark properties are not different between AC3-I and AC3-C cardiomyocytes. (PDF 178 kb)

Supplementary Methods (PDF 45 kb)

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Zhang, R., Khoo, M., Wu, Y. et al. Calmodulin kinase II inhibition protects against structural heart disease. Nat Med 11, 409–417 (2005). https://doi.org/10.1038/nm1215

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