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

Gomes, Kátia Maria Sampaio; Campos, Juliane C.; Bechara, Luiz R. G.; Queliconi, Bruno B.; Lima, Vanessa Batista de Sousa; Disatnik, Marie‐Hélène; Magno, Paulo; Chen, Che‐Hong; Brum, Patrícia Chakur; Kowaltowski, Alicia J.; Mochly‐Rosen, Daria; Ferreira, Julio Cesar Batista

doi:10.1093/cvr/cvu125

Cited by 115 publications

(106 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We next quantified amounts of ROS in ALDH2*2/1 and wild-type human fibroblasts. In line with ALDH2’s function as a detoxifying enzyme reducing aldehydic load in the cell and increasing mitochondrial integrity (2, 34), we found a significant elevation in basal amounts of ROS in ALDH2*2/1 fibroblasts compared to wild-type controls (Fig. 1C).…”

Section: Resultssupporting

confidence: 75%

“…Elevated cellular levels of 4HNE trigger a variety of deleterious effects such as a disturbance in the cell’s metabolic balance (11, 16, 32, 34) and inhibition of cell proliferation (35, 36). We also observed slower growth rates in isolated cultures of ALDH2*2/1 fibroblasts compared to wild-type control fibroblasts by measuring cellular growth and viability 48 hours after plating equal numbers of cells per group.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Characterization of the molecular mechanisms underlying increased ischemic damage in the aldehyde dehydrogenase 2 genetic polymorphism using a human induced pluripotent stem cell model system

et al. 2014

Self Cite

View full text Add to dashboard Cite

Nearly 8% of the human population carries an inactivating point mutation in the gene that encodes the cardioprotective enzyme aldehyde dehydrogenase 2 (ALDH2). This genetic polymorphism (ALDH2*2) is linked to more severe outcomes from ischemic heart damage and an increased risk of coronary artery disease (CAD), but the underlying molecular bases are unknown. We investigated the ALDH2*2 mechanisms in a human model system of induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs) generated from individuals carrying the most common heterozygous form of the ALDH2*2 genotype. We showed that the ALDH2*2 mutation gave rise to elevated amounts of reactive oxygen species and toxic aldehydes, thereby inducing cell cycle arrest and activation of apoptotic signaling pathways, especially during ischemic injury. We established that ALDH2 controls cell survival decisions by modulating oxidative stress levels and that this regulatory circuitry was dysfunctional in the loss-of-function ALDH2*2 genotype, causing up-regulation of apoptosis in cardiomyocytes after ischemic insult. These results reveal a new function for the metabolic enzyme ALDH2 in modulation of cell survival decisions. Insight into the molecular mechanisms that mediate ALDH2*2-related increased ischemic damage is important for the development of specific diagnostic methods and improved risk management of CAD and may lead to patient-specific cardiac therapies.

show abstract

Section: Resultssupporting

confidence: 75%

Section: Resultsmentioning

confidence: 99%

Characterization of the molecular mechanisms underlying increased ischemic damage in the aldehyde dehydrogenase 2 genetic polymorphism using a human induced pluripotent stem cell model system

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…The cardioprotective role of ALDH2 has been demonstrated in various models, including acute ischemia/reperfusion injury (Gong et al 2012), heart failure (Gomes et al 2014), and particularly in alcoholic cardiomyopathy (Doser et al 2009;Ma et al 2010). In fetal human cardiac myocytes in vitro, ALDH2 overexpression results in an alleviation of acetaldehyde-elicited cell apoptosis (Li et al 2006).…”

Section: Introductionmentioning

confidence: 99%

“…It seems that a potential therapeutic approach for ACM might benefit from ALDH2 upregulation. In fact, physiologic signaling cascades or pharmacological chemicals that activate ALDH2 have been suggested to contribute cardioprotection in reperfusion arrhythmias (Koda et al 2010), ischemia injury (Robador et al 2012), or postmyocardial infarction (Gomes et al 2014). Studying the regulatory pathways for ALDH2 expression in cardiomyocyte following ethanol exposure thus should provide important insights to the molecular targets of ACM treatment.…”

Section: Introductionmentioning

confidence: 99%

Increased expression of microRNA-378a-5p in acute ethanol exposure of rat cardiomyocytes

Wang

Song

Zhang

et al. 2017

Cell Stress and Chaperones

View full text Add to dashboard Cite

Alcohol abuse is a risk factor for a distinct form of congestive heart failure, known as alcoholic cardiomyopathy (ACM). Here, we investigate how microRNAs may participate in the induction of cardiomyocyte apoptosis associated with ethanol exposure in vitro. Increasing the concentrations of ethanol to primary rat cardiomyocytes resulted in elevated apoptosis assessed by annexin V and propidium iodide staining, and reduced expression of an enzyme for alcohol detoxification aldehyde dehydrogenase 2 (ALDH2). These ethanol effects were accompanied by a substantial elevation of miR378a-5p. Driving miR-378a-5p overexpression in cardiomyocytes decreased ALDH2. The specific interaction of miR-378a-5p with the 3'UTR of ALDH2 was examined by luciferase reporter assays, and we found that miR-378a-5p activity depends on a complementary base pairing at the 3′-UTR region of ALDH2 mRNA. Finally, ethanol-induced apoptosis in cardiomyocytes was attenuated in the presence of anti-miR378a-5p. Collectively, these data implicate a likely involvement of miR-378a-5p in the stimulation of cardiomyocyte apoptosis through ALDH2 gene suppression, which might play a potential role in the pathogenesis of ACM.

show abstract

“…Recentemente demonstramos uma redução na atividade enzimática da ALDH2 com a progressão da doença isquêmica cardíaca, e que o prejuízo nessa enzima mitocondrial correlaciona-se inversamente com a função cardíaca em ratos submetidos à cirurgia de constrição da artéria coronária descendente anterior (39).…”

Section: Aldeído Desidrogenase 2 (Aldh2)unclassified

Participação da enzima aldeído desidrogenase 2 na progressão da doença arterial periférica.

Ribeiro¹

View full text Add to dashboard Cite

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

Cited by 115 publications

References 38 publications

Characterization of the molecular mechanisms underlying increased ischemic damage in the aldehyde dehydrogenase 2 genetic polymorphism using a human induced pluripotent stem cell model system

Characterization of the molecular mechanisms underlying increased ischemic damage in the aldehyde dehydrogenase 2 genetic polymorphism using a human induced pluripotent stem cell model system

Increased expression of microRNA-378a-5p in acute ethanol exposure of rat cardiomyocytes

Participação da enzima aldeído desidrogenase 2 na progressão da doença arterial periférica.

Contact Info

Product

Resources

About