Approximately 6.2 million Americans suffer from heart failure, an incurable disease with a staggering mortality rate – about 40 percent of patients die within five years of being diagnosed. Heart failure is one type of heart disease, and new treatments are desperately needed.
Now, in a new work, scientists at Temple Katz Lewis School of Medicine (LKSOM) at Temple University are paving the way for a promising novel therapeutic strategy, targeting a molecule in the heart called the G protein-coupled protein kinase 5 (GRK5). In a study published online in the journal Cardiovascular Research, the scientists show in mice that reducing GRK5 levels can significantly improve survival after a heart attack.
“Previous studies have found that GRK5 is elevated in patients with heart failure,” explained Claudio de Lucia, MD, PhD, associate scientist at LKSOM’s Center for Interventional Medicine and lead author on the new study. “Our new research, in mice that have experienced myocardial infarction (heart attack), shows that GRK5 overexpression is associated with physiological changes in the heart that reduce heart activity.”
Too much GRK5 in the heart was further linked to the recruitment of more immune cells into damaged heart rate and harmful inflammation. Eventually, the combination of these factors – decreased heart function and influx of immune cells and inflammation – contributed to increased mortality in mice after a heart attack.
Dr. of Lucia and colleagues, working with Walter J. Koch, PhD, WW Smith Chair of Endowment in Cardiovascular Medicine, Professor and Chair of the Department of Pharmacology, Director of the Center for Interventional Medicine at LKSOM, and senior study of the new study, they examined GRK5 levels in the heart eight weeks after mice experienced a heart attack. Prior to that, animals had a condition known as post-ischemic heart failure, in which heart activity declines over time due to a reduced blood supply. Eventually delicate damage that blocks circulation in the heart depletes the heart cells of the oxygen and nutrients they need to keep the heart working.
After establishing a link between increased GRK5 sensitivity, decreased heart function, and decreased survival in the weeks following a heart attack, the researchers examined the effect of GRK5 treatment to reduce its levels in the heart. To do this, they developed a GRK5 pulse mouse model, in which GRK5 expression was specifically removed from heart cells.
“After a heart attack, our GRK5 beat mice had significantly better heart function and better survival loops compared to wild type mice with normal GRK5,” explained Drs. of Lucia. “This raises the possibility that GRK5 inhibition may be an operational therapeutic strategy in human patients, as well.”
The team’s future work will focus on GRK5 inhibitors and understanding their effects in animals with heart disease.
“High-selective drugs that inhibit GRK5 are already available,” Drs. of Lucia. “Our next step is to test these agents in animal models of heart failure to determine their impact on heart activity and survival.”
Dr Koch said, “Focusing on abnormal levels and GRK5 activity would represent an entirely new class of drugs. [for heart failure] that we hope will add significant and innovative value to our fight against heart disease. “
Source:
Temple University Health System
Magazine Reference:
of Lucia, C., et al. (2021) G protein-kinase receptor 5 (GRK5) contributes to weak heart activity and immune cell recruitment in post-ischemic heart failure. Cardiovascular Research. doi.org/10.1093/cvr/cvab044.