Contribution

Metallothionein (MT) is an indirect redox balance regulator which regulates nuclear factor red blood cell 2-related factor 2 (Nrf2) in the body. However, MT plays an important role in the anti-injury protection of the cardiovascular system, mainly in its inhibitory effect on ischemia-reperfusion injury. Also, the MT activation of the Nrf2 mediates intermittent hypoxia (IH) cardiomyopathy protection. ^[1]

Transgenic mice with a deletion of any Nrf2 gene (Nrf2-KO) are highly susceptible to the cardiovascular effects of intermittent hypoxia (IH) via cardiac oxidative damage, inflammation, fibrosis, and dysfunction.

Moreover, the specific overexpression in cardiomyocytes of Nrf2 (Nrf2-TG) in transgenic mice[KC1] is impervious to cardiac oxidative damage, inflammation, fibrosis, and dysfunction caused by intermittent hypoxia (IH)[KC2] . In response to IH, Nrf2 and its downstream antioxidants are strongly MT-dependent Nrf2 and may [KC3] act as a compensatory response to IH exposure by up-regulating MT (downstream antioxidant target genes) to protect the heart.

Prolonged exposure to IH reduces the binding of Nrf2 factor to the MT promoter gene, thereby inhibiting MT translation and expression. Moreover, a complex PI3K/Akt/GSK3B/Fyn signaling network provides cardio protection against IH when Nrf2 or MT is overexpressed in the heart. By activating the PI3K/Akt/GSK3B/Fyn signaling pathway, MT increaseNrf2 expression and transcriptional function in response to IH exposure. Although not yet proven, these effects suggest that it is possible to activate PI3K/Akt/GSK3B/Fyn dependent signaling pathways through cardiac MT overexpression to prevent chronic IH-induced cardiomyopathy and downregulation of Nrf2.

Therefore, Nrf2 or MT may be a potential treatment to avoid chronic IH-induced cardiomyopathy. ^[1]

Reference

Zhou, S., Yin, X., Jin, J., Tan, Y., Conklin, D. J., Xin, Y., Cai, L. (2017). Intermittent hypoxia-induced cardiomyopathy and its prevention by Nrf2 and Metallothionein. Free Radical Biology and Medicine, 112, 224-239. doi:10.1016/j.freeradbiomed.2017.07.031

^ ^a ^b Cite error: The named reference :0 was invoked but never defined (see the help page).

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Critique of Carbonic Anhydrase Mechanism Figure

Cardiovascular disease

Metallothionein (MT) is a key redox balance regulator in the body, which plays an important role in the anti-injury protection of the cardiovascular system, mainly in its inhibitory effect on ischemia-reperfusion injury. And through activation of nuclear factor red blood cell 2-related factor 2 (Nrf2) mediates intermittent hypoxia (IH) cardiomyopathy protection.^[1]

In this study, they stated the overall deletion of any Nrf2 gene (Nrf2-KO) transgenic mice is easier affected by intermittent hypoxia (IH)-induced cardiac oxidative damage, inflammation, fibrosis, and dysfunction. Moreover, the specific overexpression of cardiomyocytes of Nrf2 (Nrf2-TG) transgenic mice is impervious to cardiac oxidative damage, inflammation, fibrosis, and dysfunction caused by intermittent hypoxia(IH).

The results of the study showed that 4 weeks of IH exposure significantly reduced the binding of Nrf2 to the MT promoter gene, thereby inhibiting MT translation and translation in wild-type (WT) mice but had no effect on Nrf2-TG mice.

Moreover, the overexpression of Nrf2 or MT in the heart provides cardio protection against IH through complex PI3K/Akt/GSK3B/Fyn signaling. This evidence indicates that overexpression of cardiac MT may prevent chronic IH-induced cardiomyopathy and down-regulation of Nrf2 by activating PI3K/Akt/GSK-3β/Fyn-dependent signaling pathways.

Therefore, Nrf2 or MT may be a potential treatment to avoid chronic IH-induced cardiomyopathy.

References

Zhou, S., Yin, X., Jin, J., Tan, Y., Conklin, D. J., Xin, Y., Cai, L. (2017). Intermittent hypoxia-induced cardiomyopathy and its prevention by Nrf2 and Metallothionein. Free Radical Biology and Medicine, 112, 224-239. doi:10.1016/j.freeradbiomed.2017.07.031

^ "Free radical biology & Medicine". Free Radical Biology and Medicine. 35: i. 2003-01. doi:10.1016/s0891-5849(03)00697-x. ISSN 0891-5849. {{cite journal}}: Check date values in: |date= (help)

Revised Part I

Role of MT in Cardiovascular disease

Metallothionein (MT) is an indirect redox balance regulator which regulates nuclear factor red blood cell 2-related factor 2 (Nrf2) in the body. However, MT plays an important role in the anti-injury protection of the cardiovascular system, mainly in its inhibitory effect on ischemia-reperfusion injury. And through activation of nuclear factor red blood cell 2-related factor 2 (Nrf2) mediates intermittent hypoxia (IH) cardiomyopathy protection.

The transgenic mice with a deletion of any Nrf2 gene (Nrf2-KO) are highly susceptible to the cardiovascular effects of intermittent hypoxia (IH) via cardiac oxidative damage, inflammation, fibrosis, and dysfunction.

Moreover, the specific overexpression in cardiomyocytes of Nrf2 (Nrf2-TG) transgenic mice is impervious to cardiac oxidative damage, inflammation, fibrosis, and dysfunction caused by intermittent hypoxia(IH). In response to IH, Nrf2 and its downstream antioxidants are strongly MT-dependent Nrf2 may act as a compensatory response to IH exposure by up-regulating MT (downstream antioxidant target genes) to protect the heart.

Prolonged exposure to IH reduces the binding of Nrf2 factor to the MT promoter gene, thereby inhibiting MT translation and expression. Moreover, a complex PI3K/Akt/GSK3B/Fyn signaling network provides cardio protection against IH when Nrf2 or MT is overexpressed in the heart. By activating the PI3K/Akt/GSK3B/Fyn signaling pathway, MT increased Nrf2 expression and transcriptional function in response to IH exposure. The result state that it is possible to activate PI3K/Akt/GSK3B/Fyn dependent signaling pathways through cardiac MT overexpression to prevent chronic IH-induced cardiomyopathy and downregulation of Nrf2.

Therefore, Nrf2 or MT may be a potential treatment to avoid chronic IH-induced cardiomyopathy.

Reference

Zhou, S., Yin, X., Jin, J., Tan, Y., Conklin, D. J., Xin, Y., Cai, L. (2017). Intermittent hypoxia-induced cardiomyopathy and its prevention by Nrf2 and Metallothionein. Free Radical Biology and Medicine, 112, 224-239. doi:10.1016/j.freeradbiomed.2017.07.031

Figure

Mechanism of Nrf2 and MT in preventing IH-induced cardiac injury

Structure of a-domain of Human Metallothionein- (MT-3)


Identifiers
Symbol	Human metallothionein
PDB Code	2FJ4
Classification	Metal Binding Protein

[:0-1] Cite error: The named reference :0 was invoked but never defined (see the help page).

[:0-2] "Free radical biology & Medicine". Free Radical Biology and Medicine. 35: i. 2003-01. doi:10.1016/s0891-5849(03)00697-x. ISSN 0891-5849. {{cite journal}}: Check date values in: |date= (help)

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