TY - JOUR
T1 - MICAL1 constrains cardiac stress responses and protects against disease by oxidizing CaMKII
AU - Konstantinidis, Klitos
AU - Bezzerides, Vassilios J.
AU - Lai, Lo
AU - Isbell, Holly M.
AU - Wei, An Chi
AU - Wu, Yuejin
AU - Viswanathan, Meera C.
AU - Blum, Ian D.
AU - Granger, Jonathan M.
AU - Heims-Waldron, Danielle
AU - Zhang, Donghui
AU - Luczak, Elizabeth D.
AU - Murphy, Kevin R.
AU - Lu, Fujian
AU - Gratz, Daniel H.
AU - Manta, Bruno
AU - Wang, Qiang
AU - Wang, Qinchuan
AU - Kolodkin, Alex L.
AU - Gladyshev, Vadim N.
AU - Hund, Thomas J.
AU - Pu, William T.
AU - Wu, Mark N.
AU - Cammarato, Anthony
AU - Bianchet, Mario A.
AU - Shea, Madeline A.
AU - Levine, Rodney L.
AU - Anderson, Mark E.
N1 - Funding Information:
We thank Chip Hawkins and the Transgenic Mouse Core at Johns Hopkins University for generating our transgenic mice using CRISPR technology. We are grateful to the Johns Hopkins Genetics Resources Core Facility for their assistance with Sanger sequencing. We thank Djahida Bedja, Nadan Wang, Michelle Leppo, Christian Oeing, and the Cardiovascular Physiology and Surgery Core at Johns Hopkins University for technical assistance. We are grateful to Geumsoo Kim for providing MSRA and MSRB recombinant proteins. We thank Jinying Yang for animal model maintenance. We are grateful to Heping Cheng for providing the adenoviral construct for the GCaMP6f-Junctin nanosensor. We acknowledge Charles Steenbergen for his advice on actin fluorescence imaging analysis. We thank Harry C. Dietz and Gregg L. Semenza for helpful comments. We are grateful to Shawn Roach and Teresa Ruggle for their help with graphic art and figure preparation. This work was supported by NIH grant R35 HL140034 (to MEA). KK was supported by NIH grant T32HL007227 and AHA postdoctoral fellowship 18POST34030257. LL and RLL were supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute, grant ZIA HL000225. ACW was supported by MOST-107-2636-B-002- 001. MNW was supported by NIH grant NS079584. VNG was supported by NIH grants AG021518 and GM065204. DHG and TJH were supported by NIH grants HL134824 and HL135096. AC was supported by NIH grant R01HL124091. MAS was supported by NIH grant R01GM57001. MAB was supported by NIH grant R21NS108842 and the Mirowsky award at Johns Hopkins University.
Funding Information:
We thank Chip Hawkins and the Transgenic Mouse Core at Johns Hopkins University for generating our transgenic mice using CRISPR technology. We are grateful to the Johns Hopkins Genetics Resources Core Facility for their assistance with Sanger sequencing. We thank Djahida Bedja, Nadan Wang, Michelle Leppo, Christian Oeing, and the Cardiovascular Physiology and Surgery Core at Johns Hopkins University for technical assistance. We are grateful to Geumsoo Kim for providing MSRA and MSRB recombinant proteins. We thank Jinying Yang for animal model maintenance. We are grateful to Heping Cheng for providing the adenoviral construct for the GCaMP6f-Junctin nanosensor. We acknowledge Charles Steenbergen for his advice on actin fluorescence imaging analysis. We thank Harry C. Dietz and Gregg L. Semenza for helpful comments. We are grateful to Shawn Roach and Teresa Ruggle for their help with graphic art and figure preparation. This work was supported by NIH grant R35 HL140034 (to MEA). KK was supported by NIH grant T32HL007227 and AHA postdoctoral fellowship 18POST34030257. LL and RLL were supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute, grant ZIA HL000225. ACW was supported by MOST-107-2636-B-002-001. MNW was supported by NIH grant NS079584. VNG was supported by NIH grants AG021518 and GM065204. DHG and TJH were supported by NIH grants HL134824 and HL135096. AC was supported by NIH grant R01HL124091. MAS was supported by NIH grant R01GM57001. MAB was supported by NIH grant R21NS108842 and the Mirowsky award at Johns Hopkins University.
Publisher Copyright:
Copyright: © 2020, American Society for Clinical Investigation.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - Oxidant stress can contribute to health and disease. Here we show that invertebrates and vertebrates share a common stereospecific redox pathway that protects against pathological responses to stress, at the cost of reduced physiological performance, by constraining Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity. MICAL1, a methionine monooxygenase thought to exclusively target actin, and MSRB, a methionine reductase, control the stereospecific redox status of M308, a highly conserved residue in the calmodulin-binding (CaM-binding) domain of CaMKII. Oxidized or mutant M308 (M308V) decreased CaM binding and CaMKII activity, while absence of MICAL1 in mice caused cardiac arrhythmias and premature death due to CaMKII hyperactivation. Mimicking the effects of M308 oxidation decreased fight-or-flight responses in mice, strikingly impaired heart function in Drosophila melanogaster, and caused disease protection in human induced pluripotent stem cell-derived cardiomyocytes with catecholaminergic polymorphic ventricular tachycardia, a CaMKII-sensitive genetic arrhythmia syndrome. Our studies identify a stereospecific redox pathway that regulates cardiac physiological and pathological responses to stress across species.
AB - Oxidant stress can contribute to health and disease. Here we show that invertebrates and vertebrates share a common stereospecific redox pathway that protects against pathological responses to stress, at the cost of reduced physiological performance, by constraining Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity. MICAL1, a methionine monooxygenase thought to exclusively target actin, and MSRB, a methionine reductase, control the stereospecific redox status of M308, a highly conserved residue in the calmodulin-binding (CaM-binding) domain of CaMKII. Oxidized or mutant M308 (M308V) decreased CaM binding and CaMKII activity, while absence of MICAL1 in mice caused cardiac arrhythmias and premature death due to CaMKII hyperactivation. Mimicking the effects of M308 oxidation decreased fight-or-flight responses in mice, strikingly impaired heart function in Drosophila melanogaster, and caused disease protection in human induced pluripotent stem cell-derived cardiomyocytes with catecholaminergic polymorphic ventricular tachycardia, a CaMKII-sensitive genetic arrhythmia syndrome. Our studies identify a stereospecific redox pathway that regulates cardiac physiological and pathological responses to stress across species.
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U2 - 10.1172/JCI133181
DO - 10.1172/JCI133181
M3 - Article
C2 - 32749237
AN - SCOPUS:85090250913
SN - 0021-9738
VL - 130
SP - 4663
EP - 4678
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 9
ER -