Researchers at the Centro Nacional de Investigaciones Cardiovasculares (CNIC) in Madrid have identified a critical role for the MKK3/6p38/ signaling pathway in the development of cardiac hypertrophy. Their study, published in eLife, suggests that inhibition of p38/ may be a useful therapeutic strategy for diseases such as hypertrophic cardiomyopathy.
Due to the absence of specific inhibitors for these kinase enzymes, this technique has remained unexplored. Another member of the protein family, p38, is also shown to have an effect upon inhibition, suggesting that long-term clinical use of p38 inhibitors may damage the heart.
Stress-activated p38 kinases perform a wide variety of functions, and their deficiency has been linked to the development of steatosis, obesity, immune disorders, and cancer. They have been identified as potential therapeutic targets by the MKK3 and MKK6 genes.
Lack of MKK6 decreases the lifespan of mice, according to a longitudinal study of cardiac function in MKK6 KO mice, which progressed to cardiac dilatation and fibrosis with age. Mechanistically, lack of MKK6 increases mammalian target of rapamycin (mTOR) signaling, resulting in cardiac hypertrophy.
The MKK3/6-p38/ pathway has a major role in the development of cardiac hypertrophy, which has significant implications for the clinical use of p38 inhibitors in the long-term treatment, as they might result in cardiotoxicity.
Guadalupe Sabio, DVM, PhD, and Rafael Romero. [CNIC]The contractile cells of the heart (cardiomyocytes) contain many molecular pathways whose activation promotes cardiac hypertrophy, according to the first author and PhD student at the CNIC, Rafael Romero.
The p38 proteins regulate a wide spectrum of functions, and their dysregulation has been linked to many illnesses, making them attractive pharmacological targets for clinical use. Nevertheless, specific inhibitors have been discovered for only one of the p38 isoforms, p38.
Guadalupe Sabio, the group's principal investigator and head of research, believes the clinical findings to date have been dismal, but other proteins of the pathway, such as p38, p38, or the upstream activator MKK6, may offer alternative pharmacological targets.
The researchers examined the long-term positive effects of inhibiting MKK6, using mice genetically engineered to deficiency MKK6, and found that their mortality decreased as they grew older.
When MKK6 is absent, the activation of p38 is significantly reduced, according to the researchers, but the inactivation of p38 resulted in an unexpectedly high level of activity of another key pathway in the development of cardiac hypertrophy, the mTOR pathway.
According to Sabio, the MKK3/6p38/ pathway plays a critical role in the development of cardiac hypertrophy. This has implications for the use of p38 inhibitors to treat chronic conditions, since they may be cardiotoxic over the long term. At the same time, our findings suggest that research should focus on specific inhibitors of p38g and p38 that might be used to treat cardiac disease.