MK2-Deficient Mice Are Bradycardic and Display Delayed Hypertrophic Remodeling in Response to a Chronic Increase in Afterload.
Author
Ruiz, MatthieuKhairallah, Maya
Dingar, Dharmendra
Vaniotis, George
Khairallah, Ramzi J
Lauzier, Benjamin
Thibault, Simon
Trépanier, Joëlle
Shi, Yanfen
Douillette, Annie
Hussein, Bahira
Nawaito, Sherin Ali
Sahadevan, Pramod
Nguyen, Albert
Sahmi, Fatiha
Gillis, Marc-Antoine
Sirois, Martin G
Gaestel, Matthias
Stanley, William C
Fiset, Céline
Tardif, Jean-Claude
Allen, Bruce G
Date
2021-02-03Journal
Journal of the American Heart AssociationPublisher
American Heart Association Inc.Type
Article
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Background Mitogen-activated protein kinase-activated protein kinase-2 (MK2) is a protein serine/threonine kinase activated by p38α/β. Herein, we examine the cardiac phenotype of pan MK2-null (MK2-/-) mice. Methods and Results Survival curves for male MK2+/+ and MK2-/- mice did not differ (Mantel-Cox test, P=0.580). At 12 weeks of age, MK2-/- mice exhibited normal systolic function along with signs of possible early diastolic dysfunction; however, aging was not associated with an abnormal reduction in diastolic function. Both R-R interval and P-R segment durations were prolonged in MK2-deficient mice. However, heart rates normalized when isolated hearts were perfused ex vivo in working mode. Ca2+ transients evoked by field stimulation or caffeine were similar in ventricular myocytes from MK2+/+ and MK2-/- mice. MK2-/- mice had lower body temperature and an age-dependent reduction in body weight. mRNA levels of key metabolic genes, including Ppargc1a, Acadm, Lipe, and Ucp3, were increased in hearts from MK2-/- mice. For equivalent respiration rates, mitochondria from MK2-/- hearts showed a significant decrease in Ca2+ sensitivity to mitochondrial permeability transition pore opening. Eight weeks of pressure overload increased left ventricular mass in MK2+/+ and MK2-/- mice; however, after 2 weeks the increase was significant in MK2+/+ but not MK2-/- mice. Finally, the pressure overload-induced decrease in systolic function was attenuated in MK2-/- mice 2 weeks, but not 8 weeks, after constriction of the transverse aorta. Conclusions Collectively, these results implicate MK2 in (1) autonomic regulation of heart rate, (2) cardiac mitochondrial function, and (3) the early stages of myocardial remodeling in response to chronic pressure overload.Identifier to cite or link to this item
http://hdl.handle.net/10713/14824ae974a485f413a2113503eed53cd6c53
10.1161/JAHA.120.017791
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