Aldehyde dehydrogenase 2 activation in heart failure restores mitochondrial function and improves ventricular function and remodelling.

Abstract

AIMS:

We previously demonstrated that pharmacological activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2) protects the heart against acute ischaemia/reperfusion injury. Here, we determined the benefits of chronic activation of ALDH2 on the progression of heart failure (HF) using a post-myocardial infarction model.

METHODS AND RESULTS:

We showed that a 6-week treatment of myocardial infarction-induced HF rats with a selective ALDH2 activator (Alda-1), starting 4 weeks after myocardial infarction at a time when ventricular remodelling and cardiac dysfunction were present, improved cardiomyocyte shortening, cardiac function, left ventricular compliance and diastolic function under basal conditions, and after isoproterenol stimulation. Importantly, sustained Alda-1 treatment showed no toxicity and promoted a cardiac anti-remodelling effect by suppressing myocardial hypertrophy and fibrosis. Moreover, accumulation of 4-hydroxynonenal (4-HNE)-protein adducts and protein carbonyls seen in HF was not observed in Alda-1-treated rats, suggesting that increasing the activity of ALDH2 contributes to the reduction of aldehydic load in failing hearts. ALDH2 activation was associated with improved mitochondrial function, including elevated mitochondrial respiratory control ratios and reduced H2O2 release. Importantly, selective ALDH2 activation decreased mitochondrial Ca(2+)-induced permeability transition and cytochrome c release in failing hearts. Further supporting a mitochondrial mechanism for ALDH2, Alda-1 treatment preserved mitochondrial function upon in vitro aldehydic load.

CONCLUSIONS:

Selective activation of mitochondrial ALDH2 is sufficient to improve the HF outcome by reducing the toxic effects of aldehydic overload on mitochondrial bioenergetics and reactive oxygen species generation, suggesting that ALDH2 activators, such as Alda-1, have a potential therapeutic value for treating HF patients.

• Authors: Katia M S Gomes, Juliane C Campos, Luiz R G Bechara, Bruno Queliconi, Vanessa M Lima, Marie-Helene Disatnik, Paulo Magno, Che-Hong Chen, Patricia C Brum, Alicia J Kowaltowski, Daria Mochly-Rosen, Julio C B Ferreira
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 103 Issue 4 Pg. 498-508 (Sep 01 2014) ISSN: 1755-3245 [Electronic] England
• PMID: 24817685 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: [email protected].

Chemical References

• Mitochondrial Proteins
• Aldehyde Dehydrogenase
• Aldehyde Dehydrogenase, Mitochondrial
• Aldh2 protein, rat

Topics

• Aldehyde Dehydrogenase (metabolism)
• Aldehyde Dehydrogenase, Mitochondrial
• Animals
• Heart Failure (enzymology, physiopathology)
• Male
• Mitochondria (enzymology)
• Mitochondrial Proteins (metabolism)
• Myocardial Contraction (physiology)
• Myocytes, Cardiac (enzymology)
• Rats, Wistar
• Ventricular Function (physiology)
• Ventricular Remodeling (physiology)