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Loss of smooth muscle CYB5R3 amplifies angiotensin II–induced hypertension by increasing sGC heme oxidation
Brittany G. Durgin, … , Peter Sandner, Adam C. Straub
Brittany G. Durgin, … , Peter Sandner, Adam C. Straub
Published September 5, 2019
Citation Information: JCI Insight. 2019;4(19):e129183. https://doi.org/10.1172/jci.insight.129183.
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Research Article Vascular biology

Loss of smooth muscle CYB5R3 amplifies angiotensin II–induced hypertension by increasing sGC heme oxidation

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Abstract

Nitric oxide regulates BP by binding the reduced heme iron (Fe2+) in soluble guanylyl cyclase (sGC) and relaxing vascular smooth muscle cells (SMCs). We previously showed that sGC heme iron reduction (Fe3+ → Fe2+) is modulated by cytochrome b5 reductase 3 (CYB5R3). However, the in vivo role of SMC CYB5R3 in BP regulation remains elusive. Here, we generated conditional smooth muscle cell–specific Cyb5r3 KO mice (SMC CYB5R3–KO) to test if SMC CYB5R3 loss affects systemic BP in normotension and hypertension via regulation of the sGC redox state. SMC CYB5R3–KO mice exhibited a 5.84-mmHg increase in BP and impaired acetylcholine-induced vasodilation in mesenteric arteries compared with controls. To drive sGC oxidation and elevate BP, we infused mice with angiotensin II. We found that SMC CYB5R3–KO mice exhibited a 14.75-mmHg BP increase, and mesenteric arteries had diminished nitric oxide–dependent vasodilation but increased responsiveness to sGC heme-independent activator BAY 58-2667 over controls. Furthermore, acute injection of BAY 58-2667 in angiotensin II–treated SMC CYB5R3–KO mice showed greater BP reduction compared with controls. Together, these data provide the first in vivo evidence to our knowledge that SMC CYB5R3 is an sGC heme reductase in resistance arteries and provides resilience against systemic hypertension development.

Authors

Brittany G. Durgin, Scott A. Hahn, Heidi M. Schmidt, Megan P. Miller, Neha Hafeez, Ilka Mathar, Daniel Freitag, Peter Sandner, Adam C. Straub

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Figure 5

Ang II–treated SMC CYB5R3–KO mice are more responsive to acute BAY 58-2667–induced vasodilation than WT controls.

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Ang II–treated SMC CYB5R3–KO mice are more responsive to acute BAY 58-26...
(A) Experimental design with Ang II–treated WT (n = 4, gray) and SMC CYB5R3–KO mice (n = 4, red) receiving i.p. injections of BAY 58-2667 (1 dose/day) and changes in BP measured. (B) Acute injection (time: 0 minutes, purple arrow) with 0.04 mg/kg BAY 58-2667 resulted in no significant differences in change in MAP between WT and SMC CYB5R3–KO mice. (C) Injection of 0.04 mg/kg BAY 58-2667 (time: 0 minutes, purple arrow) results in a significant increase in change in heart rate in WT mice over SMC CYB5R3–KO at 15 minutes after injection. (D) The higher 0.4 mg/kg BAY 58-2667 dose (time: 0 minutes, purple arrow) resulted in a significant reduction in the change in MAP in SMC CYB5R3–KO mice compared with WT mice after injection, indicating SMC CYB5R3–KO mice are more sensitive to BAY 58-2667 BP-lowering effects. (E) Both WT and SMC CYB5R3–KO mice had an elevated change in heart rate after 0.4 mg/kg BAY 58-2667 injection (time: 0 minutes, purple arrow), although no differences in heart rate occurred between groups. (B–E) P value represents significant difference between WT and SMC CYB5R3–KO by 2-way repeated measures ANOVA with P < 0.05 by post hoc Sidak multiple comparison tests. Error bars are ± SEM.

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