Molecular mechanisms autonomic dysfunction and impaired cardiac contractility in critical illness

. Author manuscript; available in PMC: 2017 Feb 1.

Published in final edited form as: Crit Care Med. 2016 Aug;44(8):e614–e624. doi: 10.1097/CCM.0000000000001606

Dr. Ackland received support for travel from Baxter healthcare (talk on beta-blockers 2010); has a patent through UCL Business (patent filed related to assessment of autonomic function - patent application 1414161.8); and received support for article research from the BRITISH HEART FOUNDATION, Wellcome Trust, and Research Councils UK (RCUK). His institution received grant support from the Academy Medical Sciences/Health Foundation Clinician Scientist Award (GLA) (GLA and AVG are supported by the British Heart Foundation Programme Grant. Part of this work was undertaken at UCLH/UCL who received a proportion of funding from the UK Department of Health’s NIHR Biomedical Research Centres funding scheme). Dr. Toner’s institution has a patent through UCL Business (patent filed related to assessment of autonomic function - patent application 1414161.8). Dr. Whittle has a patent through UCL Business (patent filed related to assessment of autonomic function - patent application 1414161.8). Dr. Machhada received support for article research from the Research Councils UK (RCUK). Dr. Dyson served as a board member for Magnus Oxygen, consulted for Magnus Oxygen; is employed by Magnus Life Science/University College London, has a patent related to Magnus Oxygen and not the current manuscript, and has shares in Magnus Oxygen. Dr. Struthers’ institution received grant support from the BJA/RCOA Project grant. Dr. Minto’s institution received grant support from BJA/RCOA Project grant. Dr. Shah received support for article research from the BRITISH HEART FOUNDATION. His institution received grant support from King's College London BHF Centre of Excellence. Dr. Gourine received support for article research from the NIH, Research Councils UK (RCUK), and the British Heart Foundation. His institution received grant support from the Wellcome Trust Senior Research Fellow and British Heart Foundation Programme Grant. The remaining authors have disclosed that they do not have any potential conflicts of interest.

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Figure 3. — Afferent autonomic dysfunction promotes GRK2 over-expression via activation of NOX-2. (A) Representative M-mode echocardiography image showing impaired baseline contractility 26 days after sino-aortic denervated in a wild-type mouse, but preserved cardiac contractility 26 days after sino-aortic denervation in a representative NOX2 mutant mouse. (B) Population data for ejection fraction in wild-type or NOX-2^-/- mouse following either sham or sino-aortic denervation procedure. 3-5/experimental group; mean±SE. *Significant difference (P<0.05). (C) Similar mean arterial pressure (measured by tail-cuff occlusion) in anesthetized wild-type or NOX-2^-/- mice. (D) Immunoblot showing reduction in phospho-troponin (Ser23/24) in wild-type cardiomyocytes 10 days after bilateral sino-aortic denervation. (E) Quantitative PCR demonstrating upregulation of GRK2 mRNA expression in SAD wild-type cardiomyocytes (referenced to expression in mouse brain cortex samples). *Significant difference (P<0.01); n=4/group. (F) Quantitative PCR demonstrating upregulation of GRK5 mRNA expression in SAD wild-type cardiomyocytes, same samples as shown in panel E (referenced to expression in mouse brain cortex samples). *Significant difference (P<0.01); n=4/group. (G) Representative immunoblot for GRK2 in murine wild-type or NOX-2^-/- ventricular cardiomyocytes, ten days after sham surgery or sino-aortic denervation (SAD). Population data show change in GRK2 protein levels for SAD wild-type or NOX-2^-/- ventricular cardiomyocytes, as relative change over mean sham protein levels (* P=0.07, unpaired t-test, n=4-6/group). (H) Representative immunoblot for GRK5 in murine wild-type or NOX-2^-/- ventricular cardiomyocytes, ten days after sham surgery or sino-aortic denervation (SAD). (I) Quantitative PCR for β-arrestin 1 mRNA expression in SAD wild-type cardiomyocytes (referenced to expression in mouse brain cortex samples). *Significant difference (P<0.05); n=4/group. (J) Quantitative PCR for β-arrestin 2 mRNA expression in SAD wild-type cardiomyocytes (referenced to expression in mouse brain cortex samples). No significant differences were found between groups.

Figure 3.