Researchers at the Centro Nacional de Investigaciones Cardiovasculares (CNIC) in Madrid say they have identified a key role for the MKK3/6–p38γ/δ signaling pathway in the development of cardiac hypertrophy. Their study “MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation,” published in eLife, suggests that inhibition of p38γ/δ could be a useful therapeutic strategy for diseases such as hypertrophic cardiomyopathy.

However, this approach remains unexplored because of the lack of specific inhibitors for these kinase enzymes. The study also shows the opposite effect upon inhibition of another member of this protein family, p38α, indicating that long-term clinical use of p38α inhibitors to treat chronic disease risks damage to the heart.

“Stress-activated p38 kinases control a plethora of functions, and their dysregulation has been linked to the development of steatosis, obesity, immune disorders, and cancer. Therefore, they have been identified as potential targets for novel therapeutic strategies. There are four p38 family members (p38α, p38β, p38γ, and p38δ) that are activated by MKK3 and MKK6,” write the authors of the study.

“Here, we demonstrate that lack of MKK6 reduces the lifespan in mice. Longitudinal study of cardiac function in MKK6 KO mice showed that young mice develop cardiac hypertrophy which progresses to cardiac dilatation and fibrosis with age. Mechanistically, lack of MKK6 blunts p38α activation while causing MKK3-p38γ/δ hyperphosphorylation and increased mammalian target of rapamycin (mTOR) signaling, resulting in cardiac hypertrophy. Cardiac hypertrophy in MKK6 KO mice is reverted by knocking out either p38γ or p38δ or by inhibiting the mTOR pathway with rapamycin.

“In conclusion, we have identified a key role for the MKK3/6-p38γ/δ pathway in the development of cardiac hypertrophy, which has important implications for the clinical use of p38α inhibitors in the long-term treatment since they might result in cardiotoxicity.”

Guadalupe Sabio, DVM, PhD, and Rafael Romero. [CNIC]
The contractile cells of the heart (cardiomyocytes) contain numerous molecular pathways whose activation promotes cardiac hypertrophy. “One of these is the p38 pathway, which is activated in response to stress stimuli,” explained first author and PhD student at the CNIC, Rafael Romero.

The p38 proteins control a broad spectrum of processes, and their dysregulation has been linked to numerous diseases, making them promising pharmacological targets for clinical use. Nevertheless, specific inhibitors have been identified for only one of the p38 isoforms, p38α.

According to by group leader and principal investigator Guadalupe Sabio, DVM, PhD, “the results of clinical trials to date have been disappointing, but other proteins of the pathway, such as p38γ, p38δ, or the upstream activator MKK6, are interesting possible alternative pharmacological targets”.

With this in mind, the team investigated the safety and potential long-term negative effects of inhibiting MKK6. Using mice genetically engineered to lack MKK6, the scientists showed that the absence of this protein reduced life expectancy. These mice developed cardiac hypertrophy when young and developed cardiac dysfunction as they got older.

Using other mouse models, the researchers found that when MKK6 is absent the activation of p38α is significantly reduced. Nevertheless, inactivation of p38α promoted an unexpected activation of the other branch of the pathway, consisting of the proteins MKK3, p38γ, and p38δ. This activation induced another of the key pathways in the development of cardiac hypertrophy, the mTOR pathway.

“We have identified a key role for the MKK3/6–p38γ/δ pathway in the development of cardiac hypertrophy,” noted Sabio. “This has implications for the use of p38α inhibitors to treat chronic conditions, since they could be cardiotoxic over the long term. At the same time, our results indicate that efforts should be focused on the search for specific inhibitors of p38g and p38δ that could be used to treat cardiac disease.”

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