Table 1.
NADPH oxidase genetically modified animal models
| Gene | Type of modification | Genetic modification | Disease model | Experimental resultsa | Refs |
|---|---|---|---|---|---|
| Nox1 | Global knockout | Nox1−/y | ANGII infusion | Attenuated ANGII-induced hypertension | 222,233 |
| Nox1−/y on hph-1 background233 | ANGII infusion | Prevented eNOS uncoupling in the aorta and reduced incidence of AAA | 34 | ||
| Nox1−/y on Apoe−/− background233 | High-fat diet or STZ injection | Reduced superoxide production in the aorta and reduced aortic lesion formation | 256,257 | ||
| Nox1−/y (REF.233! | STZ injection | Inhibited aortic eNOS uncoupling and improved endothelium-dependent vasorelaxation | 26 | ||
| Vascular smooth muscle transgene | Overexpression of human NOX1 in vascular smooth muscle cells | ANGII infusion | Increased aortic superoxide production and exaggerated increase in BP in ANGII-treated animals | 235 | |
| Nox2 (Cybb) | Global knockout | Nox2−/y | ANGII infusion | Inhibited ANGII-induced superoxide production in the aorta and reduction or no change in BP at baseline or in response to ANGII infusion | 56,372 |
| Nox2−/y on hph-1 background | ANGII infusion | Prevented eNOS uncoupling in the aorta and reduced incidence of AAA | 34 | ||
| Nox2−/y on Apoe−/− background373 | High-fat diet | Reduced aortic superoxide production and reduced aortic lesion formation | 258 | ||
| Nox2−/y | Cardiac IR injury | Reduced cardiac superoxide production, attenuated cardiomyocyte apoptosis and reduced IR injury in the heart | 58 | ||
| Nox2−/y plus cardiac-specific Nox4−/− | Cardiac IR injury | Reduced superoxide production, increased cardiomyocyte apoptosis and increased IR injury in the heart | 58 | ||
| Nox2−/y | ANGII infusion or TAC | Inhibited ANGII-induced myocardial NOX activity or superoxide production, reduced cardiac fibrosis in ANGII-infused animals, and no change or attenuated cardiac hypertrophy | 292,294,372 | ||
| Endothelial transgene | Overexpression of human NOX2 in endothelial cells | ANGII infusion | Increased NOX activity or superoxide production, increased BP in ANGII-infused animals(0.3–0.4 mg/kg per day) and no change in ANGII-induced hypertension (1.1 mg/kg per day) | 236,237,372 | |
| Overexpression of human NOX2 in endothelial cells on Apoe−/− background236 | ANGII infusion | Increased endothelial superoxide production at baseline and no change in atherosclerotic lesion formation | 259 | ||
| Overexpression of human NOX2 in endothelial cells237 | ANGII infusion or left coronary artery ligation | No change in hypertrophy or infarct area | 275,372 | ||
| Cardiac transgene | Overexpression of human NOX2 in cardiomyocytes | Left coronary artery ligation | No change in infarct area and same mortality | 275 | |
| Nox4 | Global knockout | Nox4−/− | ANGII infusion | No change or decreased BP in response to ANGII infusion | 238,239 |
| Nox4−/− in Dahl salt-sensitive rats | 4.0% NaCldiet | Reduced kidney oxidative stress and attenuated BP in salt diet-treated animals | 249 | ||
| Nox4−/− on hph-1 background | ANGII infusion | Prevented eNOS uncoupling in the aorta and reduced incidence of AAA | 34 | ||
| Nox4−/− on Apoe−/− or LDlr−/− background | High-fat diet with orwithout partial carotid artery ligation, or STZ injection | Increased aortic superoxide production and increased atherosclerotic lesion formation | 243,260,261 | ||
| Nox4−/− | Cardiac IR injury | Reduced cardiac superoxide production, inhibited cardiomyocyte apoptosis and protected from IR injury in the heart | 58 | ||
| Nox4−/− | Suprarenal aortic constriction or TAC | Exaggerated cardiac fibrosis and increased cardiac hypertrophy | 134,288 | ||
| Knockdown of Nox4 by in vivo siRNA injection | Cardiac IR injury (Langendorff) | Recoupled eNOS in IR-injured heart, attenuated mitochondrialsuperoxide production and reduced cardiac IR injury | 31 | ||
| Cardiac knockout | Cardiac-specific Nox4−/− | Cardiac IR injury | Reduced cardiac superoxide production, inhibited cardiomyocyte apoptosis and protected from IR injury in the heart | 58 | |
| Cardiac-specific Nox4−/− | Phenylephrine infusion or TAC | Reduced cardiac hypertrophy | 59,134 | ||
| Global transient overexpression | Overexpression of human NOX4 | NA | Induced arrhythmic phenotype in zebrafish embryos | 60 | |
| Overexpression of dominant-negative form of human NOX4 (P437H) | NA | Abrogated arrhythmic phenotype in zebrafish embryos | 60 | ||
| Endothelial transgene | Overexpression of Nox4 in endothelial cells | ANGII infusion | Elevated H2O2 production in endothelial cells, improved endothelial-dependent vasodilatation and reduced BP in ANGII-infused animals | 241 | |
| Overexpression of Nox4 in endothelial cells on Apoe−/− background | High-fat and high-cholesterol diet | Attenuated atherosclerosis | 262 | ||
| Cardiac transgene | Inducible overexpression of Nox4 in cardiomyocytes | ANGII infusion | No change in mean BP in response to ANGII infusion | 240 | |
| Overexpression of Nox4 in cardiomyocytes89 | Cardiac IR injury (in vivo or Langendorff) | Increased ROS production and no alteration or exacerbation in cardiac IR injury | 58,276 | ||
| Overexpression of dominant-negative form of Nox4 (P437H) in cardiomyocytes89 | Cardiac IR injury (in vivo or Langendorff) | Increased superoxide production and increased IR injury in the heart | 58,276 | ||
| Overexpression of Nox4 in cardiomyocytes | Ageing, TAC or phenylephrine or ANGII infusion | Increased ROS production and apoptosis, diminished left ventricle function and increased hypertrophy (at cellular level of cardiomyocytes and at the organ level) | 59,89,134,240 | ||
| Overexpression of Nox4 in cardiomyocytes | Suprarenal aortic constriction | Increased H2O2 production in the heart at baseline, increased myocardial angiogenesis, protected from cardiac dysfunction and fibrosis, and reduced cardiac hypertrophy | 288 | ||
| Overexpression of dominant-negative form of Nox4 (P437H) in cardiomyocytes89 | Ageing | Decreased superoxide production in left ventricle and no change in cardiac fibrosis or apoptosis | 89 | ||
| Nox5 | Endothelial knock-in | Knock-in of human NOX5 in endothelial cells | Cardiac IR injury, MI orbrain IR injury (stroke–reperfusion) | No change in BP at baseline, no change in cardiac infarctsize or cardiac function aftercardiac IR injury or MI, increased ROS production after stroke, increased blood–brain barrier leakage and increased infarctsize after brain IR injury | 247 |
| Vascular smooth muscle overexpression | Overexpression of human NOX5 in vascular smooth muscle cells | STZ injection | Increased ROS production and increased diabetic nephropathy | 246 | |
| Vascular smooth muscle overexpression | Overexpression of human NOX5 in vascular smooth muscle cells | ANGII infusion | Increased ROS in the vessels and the heart, impaired endothelium-dependent vasorelaxation and no change in BP at baseline or in response to ANGII infusion | 245 | |
| Podocyte overexpression | Overexpression of human NOX5 in podocytes | STZ injection | Increased ROS production, increased BP at baseline plus further increase in response to STZ and increased renal damage in response to STZ | 248 | |
| Cyba (encoding p22phox) | Vascular smooth muscle knockout | Smooth muscle-specific Cyba−/− | High-fat diet | Reduced perivascular inflammation | 267 |
| Vascular smooth muscle overexpression | Overexpression of Cyba in vascular smooth muscle cells | ANGII infusion | Increased aortic H2O2 production and exaggerated BP increase in ANGII-treated animals | 234 | |
| Overexpression of Cyba invascular smooth muscle cells | High-fat diet | Increased skeletal mitochondrialsuperoxide production and impaired skeletal mitochondrial function | 267 | ||
| Ncf1 (encoding p47phox) | Global knockout | Ncf1−/− (REF.374) | DOCA–salt, 1% saline, left kidney removal | Increased aortic H4B bioavailability, reduced aortic superoxide and H2O2 production, and reduced BP | 13 |
| Ncf−/− on hph-1 background | ANGII infusion | Prevented eNOS uncoupling in the aorta and reduced incidence of AAA | 34 | ||
| Ncf1−/− on Apoe−/− background | High-fat, atherogenic diet | Reduced aortic ROS production and decreased lesion formation | 57 | ||
| Ncf1−/− | STZ injection | Recoupling of eNOS in STZ-injected animals | 26 | ||
| Noxo1 | Global knockdown | Knockdown of Noxo1 by in vivo siRNA injection | STZ injection | Recoupling of eNOS in STZ-injected animals | 26 |
AAA, abdominal aortic aneurysm; ANGII, angiotensin II; BP, blood pressure; DOCA, deoxycorticosterone acetate; eNOS, endothelial nitric oxide synthase; H2O2, hydrogen peroxide; IR, ischaemia–reperfusion; MI, myocardial infarction; NA, not applicable; NOX, NADPH oxidase; ROS, reactive oxygen species; siRNA, small interfering RNA; STZ, streptozotocin; TAC, transverse aortic constriction.
a
Compared with nongenetically modified animals on the same genetic background and with the same treatment.