Table 2 This table shows the roles and functions of Nedd4L in various cardiac diseases, especially hypertension.
From: Research progress of Nedd4L in cardiovascular diseases
Disease category | Involvement in the diseases | Functions and mechanisms | References |
Roles and functions of Nedd4L in cardiac diseases | |||
Hypertension | Salt-sensitive hypertension | SGKI phosphorylates and inhibits Nedd4L which is a ubiquitin ligase, thereby failing to reduce the channel expression and stimulate ion channel degradation. The phosphorylation mediated by SGK1 induces the interaction of Nedd4L with members of the 14-3-3 protein family, which in turn disrupts the ubiquitination and degradation of ENaC by Nedd4L, ultimately leads to salt-sensitive hypertension. | |
Essential hypertension | Nedd4L isoform I can interact with other isoforms and can increase sodium reabsorption, which can lead to hypertension; the A allele of SNP rs4149601 of Nedd4L was associated with increased blood pressure, with the involvement of Nedd4L. The detailed mechanism may be that this allele could reduce the ubiquitination and degradation of epithelial sodium channels, resulting in an increase in the density of epithelial sodium channels or prolonged residence time on the cell surface, which will further lead to the increasing of the epithelial sodium transportation, eventually result in hypertension. | ||
Liddle syndrome | Mutations in the β or α subunits of the PY motif in the ENaC lead to the binding capacity to the WW domain of Nedd4L decreased, thereby accelerate the cell activity of ENaC, promote apoptosis, increase the absorption of sodium ion and fluid in the distal nephron, and ultimately cause the blood volume and blood pressure elevated. | ||
Cardiomyopathy | Dilated cardiomyopathy | SCN5A-A1180V induces a 4.5mV negative inactivation offset of the mutant channel and also shows a slower recovery. This emergence of cardiac sodium ion current disturbance can greatly aggravate myocardial injury and ultimately lead to dilated cardiomyopathy. | [97] |
Diabetic cardiomyopathy | The miR-195-5p/SGK1/Nedd4L axis plays an important regulatory role in high glucose-induced cardiomyopathy. | [108] | |
Myocardial infarction | When the circNfix is overexpressed in cardiomyocytes, it can promote the binding of Nedd4L and Ybxl, resulting in the reduction of Ybxl, hence leads to the induction of cardiomyocyte proliferation, which is not beneficial to prognosis. | ||
Heart failure | The miR-454 activates the cAMP pathway through the NEDD4L/TrkA axis, which ultimately inhibits cardiomyocyte apoptosis and alleviates myocardial injury. | [118] | |
Arrhythmia | Long QT syndrome | SCN5A-p.Y1977N disrupts the common Nedd4L binding site (from PPxY to PPxN), thus prevents the process of ubiquitination. | |
