Novel Biomarker And Therapeutic Target For Heart Failure
- 詳細技術說明
- Dr. Yibin Wang, Professor of Anesthesiology, Physiology, and Medicine and Director of the Division of Molecular Medicine at UCLA David Geffen School of Medicine, and colleagues have identified branched-chain α-keto acids (BCKAs) as significant biomarkers of heart failure in mice and humans. BCKAs accumulate in tissues as a result of suppressed BCAA catabolic gene expression. Impairment of the BCAA catabolic pathway leads to impaired heart function and increased likelihood of pressure-overload induced heart failure, associated with elevated superoxide production, oxidative injury, and profound metabolic changes in the heart. The group has revealed that the inhibition of a specific kinase that targets BCKAs in the BCAA catabolic pathway can preserve heart function during pressure-overload induced heart failure in mice. These findings highlight the translational value of targeting BCAA catabolism as a therapy for heart failure. Dr. Wang and colleagues have identified a specific and potent inhibitor of a kinase, whose inhibition promotes BCKA degradation and preserves heart function in mouse models. This compound displayed potential for long-term benefit in treated mice as evidenced by significantly preserved left ventricular ejection fraction and reduced chamber dilation. This compound has the potential to be further modified to increase efficacy and decrease off-target effects, making it an attractive candidate over current small molecules for heart failure.
- *Abstract
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None
- *Principal Investigation
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Name: Haipeng Sun
Department:
Name: Yibin Wang
Department:
- 其他
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Background
Current standard therapies for heart failure mostly target neural hormonal signaling pathways with modest effectiveness in slowing down progression. These compounds include ACE inhibitors, β-blockers, and angiotensin receptor blockers. Consequently, there is a market for pursuing drugs that target the amino acid metabolic regulation pathway and that may slow down heart failure progression. Dr. Wang has been studying the molecular signaling of heart failure for over a decade and has intimate knowledge of the branched-chain amino acid (BCAA) catabolism pathway in relation to the heart. Accumulation of branched-chain alpha-keto acids (BCKA) resulting from BCAA catabolic defects directly impairs mitochondrial activity, induces oxidative stress, and promotes cardiac dysfunction. Genetic defects of BCAA catabolism have been shown to lead to Maple Syrup Urine Disease, while abnormal serum levels have been linked to neurological and cardiovascular diseases. The Wang Lab has shown that the restoration of proper BCAA catabolism by a pharmaceutical agent blunts the disease progression of pressure-overload induced heart failure.
Additional Technologies by these Inventors
Tech ID/UC Case
25861/2016-743-0
Related Cases
2016-743-0
- 國家/地區
- 美國
