Cytoglobin regulates blood pressure and vascular tone through nitric oxide metabolism in the vascular wall

Abstract

The identity of the specific nitric oxide dioxygenase (NOD) that serves as the main in vivo regulator of O2-dependent NO degradation in smooth muscle remains elusive. Cytoglobin (Cygb) is a recently discovered globin expressed in fibroblasts and smooth muscle cells with unknown function. Cygb, coupled with a cellular reducing system, efficiently regulates the rate of NO consumption by metabolizing NO in an O2-dependent manner with decreased NO consumption in physiological hypoxia. Here we show that Cygb is a major regulator of NO degradation and cardiovascular tone. Knockout of Cygb greatly prolongs NO decay, increases vascular relaxation, and lowers blood pressure and systemic vascular resistance. We further demonstrate that downregulation of Cygb prevents angiotensin-mediated hypertension. Thus, Cygb has a critical role in the regulation of vascular tone and disease. We suggest that modulation of the expression and NOD activity of Cygb represents a strategy for the treatment of cardiovascular disease.

The Hemoglobin Homolog Cytoglobin in Smooth Muscle Inhibits Apoptosis and Regulates Vascular Remodeling

“…In light of past studies indicating some level of expression of myoglobin (MB) and cytoglobin (CYGB) in vessels and to better understand the conditions associated with CYGB expression 2, 17, 18, 21 , we first compared CYGB mRNA levels to those of myoglobin ( MB) using quantitative real-time polymerase chain reaction (qPCR). Overall, human aortic samples showed statistically significantly higher mRNA levels for CYGB than MB (Figure 1A).…”

“…In the cardiovascular system, CYGB is expressed in the heart and increases during hypoxia-induced cardiac hypertrophy in the mouse 16 . CYGB mRNA and protein are also found in human and rodent vascular smooth muscle (VSM) 17 and recent evidence for a role for CYGB as a regulator of NO homeostasis in vivo has been provided 18 . However, the functional significance of CYGB expression in the context of vascular remodeling is unknown.…”

Cytoglobin at the Crossroads of Vascular Remodeling

“…21 Recent data from our group and others show a highly efficient reduction of Cygb by the NADH/CYB5/CYB5R3 reducing system; in fact, the reduction of Cygb is at least an order of magnitude faster than that of other heme globins. 23, 24 Taken together, these results suggest the existence of a Cygb/CYB5/CYB5R3 metabolon in vascular SMCs, enabling rapid consumption of NO and thus modulating NO bioactivity and signaling. Interestingly, Mb in vascular smooth muscle has previously been shown to contribute to hypoxic vasodilation via nitrite reduction to NO.…”

“…18 NO dioxygenation is considered to significantly contribute to NO metabolism in vivo , with physiologic effects including cytoprotection and regulation of vascular tone. 16, 19–23 For example, endothelial Hb α, localized to myoendothelial junctions, has been shown to consume NO generated in the endothelium, regulating vascular tone. 21 Inhibition of this NO consumption results in significant decreases in blood pressure.…”

“…22 Loss of Cygb in the SMCs appears to elicit similar effects, showing increased vasodilation and decreased blood pressure in Cygb knockout mice. 23 …”