University Article Review: NADPH Oxidase and Cardiovascular Pathology

This report reviews a scientific journal article that explores the role of NADPH oxidase (Nox) family members, specifically Nox1, Nox2, Nox4, and Nox5, in the pathophysiology of various cardiovascular diseases. The article highlights how these Nox enzymes, particularly Nox2 and Nox4, contribute to oxidative stress, inflammation, and vascular dysfunction, leading to conditions like hypertension, atherosclerosis, cardiac hypertrophy, and heart failure. It details the mechanisms by which Nox enzymes influence smooth muscle contraction, macrophage activation, and angiogenesis. The review also discusses the controversial role of Nox4 in hypertension and the protective effects observed in Nox1-deficient mice. Furthermore, the report emphasizes the involvement of Nox enzymes in ischemic models of brain, heart, and lungs, including myocardial infarction and neurodegeneration, underscoring their critical role in modulating cardiovascular physiology and pathology by influencing cell proliferation, differentiation, apoptosis, and inflammatory responses. The overall conclusion emphasizes the importance of understanding Nox homologues for developing therapeutic strategies for cardiovascular diseases.

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NADPH oxidase (Nox) is an important marker for cardiovascular diseases like
hypertension, atherosclerosis, cardiac hypertrophy, remodeling collateral formation,
angiogenesis, stroke and heart failure. 4 catalytic subunits of Nox (Nox 1, 2, 4 and 5) are
expressed in tissues of cardiovascular system and promotes disease development.
The first recruited member of the family of NADPH oxidase is Nox2. Nox2 is
responsible for the reduction of molecular oxygen species into super-oxide ion (reactive
oxygen species or ROS) and thus Nox2 in excess lead to the development of oxidative stress
and thereby promoting cardiovascular disease. Moreover, ROS produced rapidly neutralize
NO (nitric oxide) and thus up-regulation of Nox2 leads to the impairment of the NO-
mediated smooth muscle relaxation and thereby promoting vessel contraction. Nox2
activation has proinflammatory influence as has direct influence over the macrophage
activation along with the release of the pro-inflammatory cytokines. This pro-inflammatory
response coupled with the Nox2 mediated xanthine mediated ROS release further strengthens
its influence over the development of cardiovascular disease.
Nox1 plays an active role in host defense in colon epithelium while facilitating
oxidase assembly via binding with activator subunit and p22phox. Nox1 binds with p22phox,
forming membrane bound cytochrome complex. The exact framework of Nox1 is still not
known but it is assumed to be similar with other Nox enzymes like having an identical FAD,
NADPH and dehydrogenase-binding domain. Nox1 is also found in plasma membrane and
main biochemical function of vascular Nox1 is production of superoxide. Nox5 stimulates
smooth muscle contraction of ovary under the influence of the calcium ion flux.
Distribution of Nox4 is abundant in kidney cortex however, it is ubiquitously
expressed in cardiovascular system and macrophages responsible for atherosclerosis. Nox2 is

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co-expressed at higher level along with Nox1 and Nox2, under the influence of TGF-β, TNF-
α and oxidized 1-palmitoyl-2-arachidonyl-sn-glycerol-3phosphocholine (Ox-PAPC. TNF-α
induced apoptosis is in turn dependent on Nox4. Association of p22phox activates Nox4 and
mutation in the hem binding histidine (115) diminishes the interaction of Nox4 with p22phox.
Nox4 also leads to the formation of ROS. Nox4 is upregulated under the action of cellular
stress and down regulated by pulsatile flow or cyclic strain. Upregulation of Nox4 promotes
differentiation of the vascular smooth muscle cells (VSMCs) that promotes the formation of
atherosclerotic lesions. Moreover over-expression of Nox4 decreases the migration of
VSMCs and also promotes aging. Down regulation of Nox2 in ribozymes decrease cardiac
commitment.
NADPH oxidase is an important source of ROS and which in turn is the driving cause
behind hypertension. Among NOX family, the role of Nox4 in hypertension is quite
controversial. This is because, the level of Nox4 remains elevated in several hyper tension
models of vasculature but not in others. However, Nox1 is directly related towards the
occurrence of atherogenesis. For example, Nox1 deficient mice with infused proactherogenic
peptide (AngII) remains shielded from aortic dissection. This is because, they secrete
increased levels of tissue inhibitor of metalloproteinase. However, the mechanism behind the
over-expression of Nox and subsequent activity of atherosclerotic arteries is still not clear.
However, much less information is present about the role of Nox4 in arthrosclerosis lesion
formation.
In development of angiogenesis, Nox1 plays a significant role and this is
demonstrated in the Nox1 deficient mice which shows upregulation under the influence of
proangiogenic factors. Nox1 also promotes tumor angiogenesis via inhibiting antiangiogenic
factor, PPARα. Moreover, Nox1-expressing NIH3t3 cell line when injected into athymic ice
lead to the formation of vascularized tumors under the over-expression of VEGF and

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increased MMP-9 activity. However, the transplantation of Nox2 deficient mice restores the
recovery of blood flow. On contrary, Nox2-deficient knockout mice remains protected
against the neovascularization loss, which is inflicted via diabetes or hypercholesterolemia.
NADPH oxidases have active influence in the pathophysiology of the disease model
of ischemis of brain, heart and lungs. Among the NADPH oxidases, there lies an active
relation between Nox4 and Nox2. This is because Nox2 activation activates Nox4. This
transient activation of Nox4 under the influence of Nox2 is observed during the endothelin
induced cardio vascular accident and showcasing active influence of Nox2 and Nox4 in
disease development. Upregulated Nox4 induce neurodegeneration in ischemic mice model
and thereby giving active evidence of Nox4 in cardio vascular disease.
Nox4 also plays an important role in the myocardial infarction (MI). This is indicated
during the surgical ligation of coronary artery of left anterior side that induces an exponential
increase in Nox4 expression in brain (paraventricular nucleus). Nox2 and Nox4 are two most
expressed Nox homologs in the cardiac tissues and thus have an active influence over the
cardiac hypertrophy and post mycocardial infraction. These homologues work in a co-
ordinate manner to contribute blood pressure regulation and controlling other notable cardiac
activity.
Thus from the above summarized version of the scientific journal article, it can
interpreted that Nox homologue proteins play an essential role modulating the cardiovascular
pathophysiology and cardiovascular physciology. Nox homologues play an active role in
modulating the proliferation, differentiation and apoptosis of the cardiac and oxygen sensing
cells. Its further influence over the inflammatory response, transcription factors and ion
channels provide a clear evidence towards its role in influencing the development of the
numerous cardiovascular disease either via substantial upregulation or downregulation.

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