When the heart begins to fail, the body does everything in its power to fix the situation. But sometimes, those compensatory mechanisms ultimately do more harm than good. Such is the case with the adrenal hormone aldosterone, which stimulates the heart to pump harder, causing greater damage to the heart muscle.

Now researches in the journal Nature Communications have identifies an unexpected mechanism by which signaling molecules known as G protein-coupled receptor kinases (GRKs) mediate aldosterone-induced heart damage.

"It turns out that two kinases, GRK2 and GRK5, contribute to the pathology of heart failure by inducing specific changes in myocytes (heart cells) down-stream of mineralocorticoid receptors that bind aldosterone," explained the senior author.

Researchers treated heart cells in vitro with aldosterone and looked at the effects on various receptors, they found a direct correlation between AT1R and aldosterone. However, events downstream of AT1R activation were not consistent with traditional GPCR mechanisms. In fact, subsequent in vitro experiments revealed a non-GPCR mechanism, whereby GRK2 and GRK5 are directly involved in triggering pathways leading to cardiac damage via mineralocorticoid receptor activation.

The pathological significance of that mechanism was borne out in studies in vivo, in which mice treated with high doses of aldosterone exhibited increased levels of GRK2 and GRK5, with kinase translocation to mitochondria and the cell nucleus negatively affecting cardiac function. Experiments in aldosterone-treated knock-out mice showed that the loss of GRK2 significantly attenuated cell death along mitochondrial pathways, protecting mice from aldosterone-induced heart damage. The loss of GRK5 was also protective, though to a lesser degree.

The team further analyzed lymphocytes from heart failure patients to confirm the clinical significance of GRK2 and GRK5 in the context of hyperaldosteronism. Patients taking spironolactone, an aldosterone inhibitor, had lower GRK2 levels in their lymphocytes compared to patients who were not taking the drug. Previous studies had shown that in humans GRK levels in lymphocytes correlate with GRK levels in the heart.

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