Nitric oxide implicated in heart failure and drug efficacy

Nitric oxide may play a pivotal role in the efficacy of cardiac drugs, and nitric oxide levels may affect the severity of heart failure, according to a recent study in Molecular Cell.

“We have identified a main function of nitric oxide in cellular systems,” said corresponding author Jonathan S. Stamler, MD, Institute for Transformative Molecular Medicine, Case Western Reserve University, Cleveland, OH. “It likely regulates GPCR signaling across virtually all cell types and tissues. This may bear directly on numerous diseases as well as the predicted response to therapeutic agents.”

G protein-coupled receptors (GPCRs) lie on cellular membranes and serve as targets for almost one-third of FDA-approved drugs. Once bound, these receptors activate either of two pathways. The first pathway involves G proteins that are of clinical benefit, and the second, β-arrestins (βarrs), can yield adverse effects. Results from previous studies indicate such signals are biased, with one pathway becoming more active than another.

“We considered that signaling bias might be endogenously regulated by a mechanism common to multiple GPCRs, and in particular, that post-translational regulation of βarrs by the ubiquitous signaling molecule nitric oxide (NO) might provide such a mechanism,” wrote the authors.

Dr. Stamler and colleagues genetically engineered mice to lose their ability to trigger the arrestin pathway, which resulted in a heart failure exacerbation in the animal models.

“Without nitric oxide signaling, they could not increase heart rate or pump function,” said Dr. Stamler. “Without nitric oxide, heart rate and contractility can’t increase, and thus hearts fail,”

The team verified their discovery using human tissue samples procured from heart transplants. Nitric oxide determined signaling balance to the arrestin pathway in nearly two-thirds of heart failure samples. Moreover, many of these hearts demonstrated evidence of nitric oxide deficiency and arrestin activation.

“Our results suggest that the balance between G protein—vis-à-vis βarr-mediated transduction, reflecting the status of βarr S-nitrosylation, serves as a previously unrecognized determinant of adrenergic responsivity in the heart and of cardiac function generally,” wrote the authors.

They suggest that G-protein bias could be a common feature of heart failure, and that heart failure can manifest in different ways based on the availability of nitric oxide. More specifically, nitric oxide may help cardiac drugs work better; whereas, deficiencies in nitric oxide could activate the arrestin pathway and adverse effects, as well as lay the foundation for heart failure by increasing susceptibility to stressors by failing to activate G proteins.

Finally, these findings have clinical implications with respect to drug design.

“Drugs and hormones inevitably regulate both pathways, but if one could shut down the pathway producing side effects, drugs would work better,” said Dr. Stamler. “In the new study, we have discovered how nature signals without side effects. It is able to use nitric oxide to shut down arrestin-based pathways causing side effects.”

He concluded: “Our work shows that the main receptors in the heart that respond to drugs don’t work without nitric oxide. The study provides new motivation to replace nitric oxide during heart failure.”