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. 2021 Jul;14(4):1512-1523.
doi: 10.1111/cts.13015. Epub 2021 May 1.

Angiotensin 1-7 protects against ventilator-induced diaphragm dysfunction

Toshinori Yoshihara  1   2 , Rafael Deminice  1   3 , Hayden W Hyatt  1 , Mustafa Ozdemir  1 , Branden L Nguyen  1 , Scott K Powers  1
Affiliations

Angiotensin 1-7 protects against ventilator-induced diaphragm dysfunction

Toshinori Yoshihara et al. Clin Transl Sci. 2021 Jul.

Abstract

Mechanical ventilation (MV) is a life-saving instrument used to provide ventilatory support for critically ill patients and patients undergoing surgery. Unfortunately, an unintended consequence of prolonged MV is the development of inspiratory weakness due to both diaphragmatic atrophy and contractile dysfunction; this syndrome is labeled ventilator-induced diaphragm dysfunction (VIDD). VIDD is clinically important because diaphragmatic weakness is an important contributor to problems in weaning patients from MV. Investigations into the pathogenesis of VIDD reveal that oxidative stress is essential for the rapid development of VIDD as redox disturbances in diaphragm fibers promote accelerated proteolysis. Currently, no standard treatment exists to prevent VIDD and, therefore, developing a strategy to avert VIDD is vital. Guided by evidence indicating that activation of the classical axis of the renin-angiotensin system (RAS) in diaphragm fibers promotes oxidative stress and VIDD, we hypothesized that activation of the nonclassical RAS signaling pathway via angiotensin 1-7 (Ang1-7) will protect against VIDD. Using an established animal model of prolonged MV, our results disclose that infusion of Ang1-7 protects the diaphragm against MV-induced contractile dysfunction and fiber atrophy in both fast and slow muscle fibers. Further, Ang1-7 shielded diaphragm fibers against MV-induced mitochondrial damage, oxidative stress, and protease activation. Collectively, these results reveal that treatment with Ang1-7 protects against VIDD, in part, due to diminishing oxidative stress and protease activation. These important findings provide robust evidence that Ang1-7 has the therapeutic potential to protect against VIDD by preventing MV-induced contractile dysfunction and atrophy of both slow and fast muscle fibers.

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Conflict of interest statement

The authors declared no competing interests for this work.

Figures

Figure 1
Figure 1
Changes in the blood pressure during 12 h of mechanical ventilation (MV). Values are presented as means ± SD. CON, control; Saline MV, 12 h MV with saline; angiotensin (Ang)1‐7 SB, 12 h of spontaneous breathing (SB) with Ang1‐7 infusion; Ang1‐7 MV, 12 h of MV with Ang1‐7 infusion. Θ = Ang1‐7 SB different (p < 0.05) from both Saline MV and Ang1‐7 MV
Figure 2
Figure 2
Diaphragm specific force. (a) 15, (b) 30, (c) 60, and (d) 100 Hz. Values are presented as means ± SD. * = different (p < 0.05) from CON. # = different (p < 0.05) from Ang1‐7 SB. Ang, angiotensin; CON, control; MV, mechanical ventilation; SB, spontaneous breathing
Figure 3
Figure 3
Myofiber cross‐sectional area in the costal diaphragm. (a) Type IIx/b, (b) type IIa, and (c) type I. Values are presented as means ± SD. * = different (p < 0.05) from CON; # = different (p < 0.05) from Ang1‐7 SB; § = different (p < 0.05) from Ang1‐7 MV. Ang, angiotensin; CON, control; MV, mechanical ventilation; SB, spontaneous breathing
Figure 4
Figure 4
Impact of Ang1‐7 infusion on mitochondrial respiration (a), hydrogen peroxide emission (b), and expression of four hydroxynonenal (c), in the diaphragm. Values are presented as means ± SD. * = different (p < 0.05) from CON; # = different (p < 0.05) from Ang1‐7 SB; § = different (p < 0.05) from Ang1‐7 MV. Ang, angiotensin; CON, control; MV, mechanical ventilation; RCR, respiratory control ratio; SB, spontaneous breathing
Figure 5
Figure 5
E3 ubiquitin ligase Atrogin‐1 (a) and MuRF1 (b) mRNA and ubiquitinated protein (c) expression in the diaphragm. Values are presented as means ± SD. Log2 fold changes are shown for Atrogin‐1 and MuRF1 mRNA levels. * = different (p < 0.05) from CON; # = different (p < 0.05) from Ang1‐7 SB; § = different (p < 0.05) from Ang1‐7 MV. Ang, angiotensin; CON, control; MV, mechanical ventilation; RCR, respiratory control ratio; SB, spontaneous breathing
Figure 6
Figure 6
Levels of the 145 kDa (a) and 120 kDa (b) α‐II spectrin breakdown product in the diaphragm. Values are presented as means ± SD. * = different (p < 0.05) from CON; # = different (p < 0.05) from Ang1‐7 SB; § = different (p < 0.05) from Ang1‐7 MV. Ang, angiotensin; CON, control; MV, mechanical ventilation; RCR, respiratory control ratio; SB, spontaneous breathing
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