(Philadelphia, PA) - 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. But now, researchers at the Lewis Katz School of Medicine at Temple University (LKSOM) are closer than ever to putting the brakes on that process. With their recent discovery of an unexpected mechanism by which signaling molecules known as G protein-coupled receptor kinases (GRKs) mediate aldosterone-induced heart damage, they have opened the path to an important therapeutic advance.
"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 Dr. Walter J. Koch, PhD, William Wikoff Smith Endowed Chair in Cardiovascular Medicine, Professor and Chair of the Department of Pharmacology, Director of the Center for Translational Medicine at LKSOM and senior investigator on the new study. The report, published online March 2 in the journal Nature Communications, is the first to shed light on the unique interaction.
"When aldosterone binds to its receptor, GRK2 moves to the mitochondria, where it stimulates pro-death pathways, and GRK5 moves to the cell nucleus, where it activates pathways that cause heart cells to grow, making them less efficient," Dr. Koch said.
The findings were surprising because GRKs in the heart typically regulate cell signaling pathways based on interactions with G protein-coupled receptors (GPCRs), which differ structurally and functionally from mineralocorticoid receptors. The ability of GRK2 and GRK5 to operate in this so-called non-canonical or non-GPCR fashion adds to a growing body of evidence that suggests GRKs do far more than just regulate GPCRs.
The idea to investigate the relationship between heart failure, GRKs, and hyperaldosteronism (the overproduction of aldosterone) originated with Alessandro Cannavo, PhD, a post-doctoral fellow in the Center for Translational Medicine at LKSOM and first author on the new paper. "Some of the cardiac effects of aldosterone are the result of interactions between mineralocorticoid receptors and the angiotensin II type-1 receptor (AT1R), a GPCR involved in heart failure," Dr. Cannavo explained. "This led us to consider GRK2 and GRK5, which regulate AT1Rs. Both kinases also occur in the heart and are linked to heart failure."
When Dr. Cannavo and colleagues 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.
Dr. Koch's 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.
According to Dr. Koch, the findings set the stage for the advance of clinically relevant animal models and strengthen the case for the development of novel GRK2 and GRK5 inhibitors. "Both kinases are implicated in additional pathways that impact the progression of heart failure," he explained. "It could turn out that one drug, possibly a GRK2 inhibitor, would replace three drugs currently used in the treatment of heart failure. Proof for that could come down the road in the future studies."
Also contributing to the work were Daniela Liccardo, Akito Eguchi, Christopher J. Traynham, and Jessica Ibetti in the Department of Pharmacology and Center for Translational Medicine at LKSOM; Katherine J. Elliott and Satoru Eguchi in the Department of Physiology and Cardiovascular Research Center at LKSOM; and Dario Leosco, Nicola Ferrara, and Giuseppe Rengo in the Department of Translational Medical Science, University of Naples Federico, Italy.
The research was supported by National Institutes of Health grants R37 HL061690, RO1 HL088503, P01 HL08806, P01 HL075443, P01 HK091799, and HL128324.
About Temple Health
Temple University Health System (TUHS) is a $1.6 billion academic health system dedicated to providing access to quality patient care and supporting excellence in medical education and research. The Health System consists of Temple University Hospital (TUH), ranked among the "Best Hospitals" in the region by U.S. News & World Report; TUH-Episcopal Campus; TUH-Northeastern Campus; Fox Chase Cancer Center, an NCI-designated comprehensive cancer center; Jeanes Hospital, a community-based hospital offering medical, surgical and emergency services; Temple Transport Team, a ground and air-ambulance company; and Temple Physicians, Inc., a network of community-based specialty and primary-care physician practices. TUHS is affiliated with the Lewis Katz School of Medicine at Temple University.
The Lewis Katz School of Medicine (LKSOM), established in 1901, is one of the nation's leading medical schools. Each year, the School of Medicine educates approximately 840 medical students and 140 graduate students. Based on its level of funding from the National Institutes of Health, the Katz School of Medicine is the second-highest ranked medical school in Philadelphia and the third-highest in the Commonwealth of Pennsylvania. According to U.S. News & World Report, LKSOM is among the top 10 most applied-to medical schools in the nation.
Temple Health refers to the health, education and research activities carried out by the affiliates of Temple University Health System (TUHS) and by the Katz School of Medicine. TUHS neither provides nor controls the provision of health care. All health care is provided by its member organizations or independent health care providers affiliated with TUHS member organizations. Each TUHS member organization is owned and operated pursuant to its governing documents.