Researchers here report on a mechanism by which increased cellular stress in heart tissue can disrupt the regulation of the heartbeat, thus leading to arrhythmia and potentially fibrillation. The accumulated molecular damage of aging, of course, provides increased contributions to cell stress, whether from inflammatory signaling, mitochondrial dysfunction, increased presence of molecular waste, or other causes. When researchers characterize more of the ways in which regulatory pathways in cells can produce maladaptive reactions to this damage, they tend to then search for means to alter the response, rather than means to repair the underlying damage. More focus should go towards damage repair in the research community, but that that is largely not the way in which research and development progresses.
Ventricular fibrillation is the most frequent cause of sudden cardiac death. Although aging is an established risk factor for the development of cardiac arrhythmia, the mechanisms underlying this connection have been hard to pin down, hindering progress toward the development of specific treatments. With the development of an arrhythmia, the cardiac cycle speeds up and becomes irregular, with potentially life threatening consequences.
Working with animal models, researchers discovered a connection between the development of ventricular fibrillation and the activation of two key signaling proteins, the stress kinases p38γ and p38δ. This discovery opens the way to new possible intervention strategies for this condition. When the scientists examined the hearts of old mice, they found that the activation of p38γ and p38δ was increased. A similar increase in the activity of these enzymes was also observed in the hearts of mice with a genetic or pharmacologically induced predisposition to developing ventricular arrhythmias. Together, these results suggest that stress signaling via p38γ and p38δ likely plays an important role in the development of this condition.
The scientists found that p38γ and p38δ phosphorylate a receptor called ryanodine receptor 2 and another protein called SAP97, resulting in a mislocalization of the potassium ion channel Kv4.3. These molecular changes lead to premature ventricular activation and an increased susceptibility to ventricular fibrillation. The study findings identify a promising therapeutic target for the development of new strategies to prevent sustained ventricular fibrillation and provide protection against this serious condition.
Link: https://www.cnic.es/...rapeutic-target
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