Researchers have discovered a previously unknown pathological cellular mechanism underpinning heart failure, which currently has no cure, and identified a drug that can reverse the damaging malfunction. The findings open the door to a novel intervention to improve outcomes in people with the condition.
With an estimated prevalence of 64 million people worldwide, heart failure is a rapidly growing public health issue. Rather than being a specific disease, heart failure is a clinical syndrome characterized by a reduced ability of the heart to pump enough blood to meet the body’s needs for blood and oxygen.
Despite advances in treatment, heart failure continues to be associated with high mortality and morbidity and reduced quality of life. To address this, researchers from the University of São Paulo (USP) examined the cellular dysfunction that drives heart failure and identified a molecule that can reverse it.
USP researchers had previously shown that heart failure is associated with malfunctioning mitochondria, normally responsible for powering the body’s cells, something the researchers liken to a car engine.
“When a car engine isn’t running properly, energy conversion is impaired, efficiency drops, and pollution increases,” said Julio Ferreira, co-corresponding author of the study.
The ‘pollutant’ Ferreira is referring to is the toxic aldehyde 4-hydroxynonenal (4-HNE), a byproduct of mitochondrial dysfunction in heart failure.
“Every cell has hundreds or sometimes thousands of mitochondria, which produce enough aldehyde to poison the entire cell when they aren’t running properly,” Ferreira said. “We discovered in this latest study that too much of 4-hydroxynonenal switches off a vital event for the cell: processing of microRNAs.”
microRNAs (miRNAs) are small, non-coding RNAs that play an important role in gene regulation. Disruption of miRNA formation is associated with several diseases, including cancer, neurodegenerative and cardiovascular disorders.
Using mass spectrometry, the researchers observed that 4-HNE irreversibly binds to and inactivates Dicer, an enzyme encoded by the DICER1 gene essential to miRNA formation. It’s a mechanism that hadn’t been seen before.
“In this study, we identified the chemical alterations that inactivate Dicer in rodents and humans owing to the accumulation of aldehyde caused by heart failure,” Ferreira said. “This was a hitherto unknown mechanism. The point is that Dicer is a limiting enzyme for formation and maturation of the microRNAs responsible for overall control of cellular biology.”
Using a drug called AD-9308 on samples of human heart tissue, the researchers were able to restore Dicer activity and reverse the effect of heart failure, improving cardiac function in rodent models. In a previous study, AD-9308 was shown to activate mitochondrial aldehyde dehydrogenase 2 (ALDH2), the major enzyme that detoxifies 4-HNE, to effectively treat cardiomyopathy in mice.
“In summary, AD-9308 stimulates the removal of aldehyde from sick cells, reducing the likelihood that it will ‘switch off’ Dicer and hence protecting the heart cells,” said Ferreira. “This tends to keep the microRNA profile closer to that of a healthy heart.”
The researchers partnered with Foresee Pharmaceuticals, a Taiwan- and US-based biopharmaceutical company and the producers of AD-9308 for the study.
The current study not only provides a new insight into the mechanisms involved in heart failure but opens the door to a novel therapeutic intervention to improve outcomes in people with the condition.
The study was published in the European Heart Journal.
Source: Agência FAPESP