Potential of gene therapy as a treatment for heart failure

Hajjar, Roger J.

doi:10.1172/jci62837

Cited by 77 publications

(75 citation statements)

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“…[1][2][3][4] The incidence of CHF in adults is nearly 1~2% in developed countries and is above 10% among patients older than 70 years of age. 5) Synthetic treatments and assist devices have been introduced to improve myocardial remodeling, strengthen myocardial contraction, and alleviate cardiac overload.…”

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confidence: 99%

Effect of Allopurinol on Myocardial Energy Metabolism in Chronic Heart Failure Rats After Myocardial Infarct

et al. 2016

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SummaryTo determine the effect of the xanthine oxidase (XO) inhibitor allopurinol on myocardial energy metabolism in a chronic heart failure rat model after myocardial infarct.An AMI model was established in 6-week-old rats via the ligation of the anterior descending coronary artery. Thirty-five rats were randomly divided into the following 3 groups: an ALLO group, an AMI group, and a Sham group. Heart failure was successfully diagnosed via echocardiography and blood tests. Xanthine oxidase (XO), malondialdehyde (MDA), PGC-1α, CPT-1, and GLUT4 were monitored in the myocardium.The TEM results demonstrated that myofilament lysis and mitochondrial swelling were alleviated in the ALLO group compared with the AMI group (without ALLO). The results also demonstrated that cardiac function was significantly improved in the ALLO group compared with the AMI group. Compared with the AMI group, the ALLO group exhibited increased respiratory-chain enzyme activity, as well as increased PGC-1α and CPT-1 mRNA and protein expression, decreased MDA content, and decreased XO and GLUT4 mRNA and protein expression.ALLO improves myocardial energy metabolism in rats with chronic heart failure, which may result from the regulation of PGC-1α in the setting of glycolipid metabolism, enhancing the production of ATP. (Int Heart J 2016; 57: 753-759) Key words: Reactive oxygen species (ROS), Mitochondria C hronic heart failure (CHF) is the terminal stage of heart disease and is the leading cause of death in affected patients. 1-4) The incidence of CHF in adults is nearly 1~2% in developed countries and is above 10% among patients older than 70 years of age.5) Synthetic treatments and assist devices have been introduced to improve myocardial remodeling, strengthen myocardial contraction, and alleviate cardiac overload. 6,7)Editorial p.661 Improving cardiomyocyte energy metabolism has attracted attention as a potential therapy for CHF. As early as 1934, Decherd, et al 8) observed that cardiomyocytes exist in a state of "energy starvation" in the setting of CHF. Recent studies have demonstrated that the activity of respiratory-chain enzymes decreases and changes in glycolipid metabolism in the setting of CHF, resulting in decreased myocardial ATP production. Additionally, the levels of reactive oxygen species (ROS) increase rapidly following myocardial infarction. An important source of reactive oxygen species ROS, 9,10) xanthine oxidase (XO), is over-expressed in CHF, 11,12) causes mitochondrial injury, and inhibits the activity of various respiratory-chain enzymes.13) Additionally, increased evidence indicates that cardiomyocyte glycolipid metabolism is disrupted in CHF. 14,15) Opie, et al 16) observed increased concentrations of high-energy phosphate among patients with CHF following the intravenous administration of ALLO, an XO inhibitor. However, the mechanisms underlying the activity of ALLO in the setting of CHF remain poorly understood. In this study, rat models of CHF introduced via the ligation of coronary arteries were constructe...

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Effect of Allopurinol on Myocardial Energy Metabolism in Chronic Heart Failure Rats After Myocardial Infarct

et al. 2016

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“…In support of this hypothesis, Carabin overexpression attenuated hypertrophic signaling and protected the heart against hypertrophic remodeling. Cardiac gene therapy has emerged as a promising approach for treating HF, supported by a growing number of positive preclinical studies 32 and a recent successful result in phase II study (the Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease [CUPID] trial) targeting the cardiac sarcoplasmic/ endoplasmic reticulum Ca 2+ ATPase pump. 33 Our findings that restoration of Carabin expression with AAV9-Carabin improves cardiac function in mice with HF suggest that Carabin gene transfer may provide a novel therapeutic strategy for the treatment of HF.…”

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Carabin Protects Against Cardiac Hypertrophy by Blocking Calcineurin, Ras, and Ca ²⁺ /Calmodulin-Dependent Protein Kinase II Signaling

et al. 2015

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C ardiac hypertrophy, the compensatory response of the heart to stress, is characterized by nonmitotic growth, the addition of new sarcomeres, and fetal gene expression. 1 However, prolonged hypertrophy of the myocardium can progress to heart failure (HF), a leading cause of morbidity and mortality, often associated with sudden cardiac death. 2-4Thus, understanding the signaling mechanisms that regulate pathological cardiac hypertrophy may lead to a better treatment for patients with HF.The hypertrophic growth of the myocardium is typically initiated by signal transduction pathways in response to Background-Cardiac hypertrophy is an early hallmark during the clinical course of heart failure and is regulated by various signaling pathways. However, the molecular mechanisms that negatively regulate these signal transduction pathways remain poorly understood. Methods and Results-Here, we characterized Carabin, a protein expressed in cardiomyocytes that was downregulated in cardiac hypertrophy and human heart failure. Four weeks after transverse aortic constriction, Carabin-deficient (Carabin −/− ) mice developed exaggerated cardiac hypertrophy and displayed a strong decrease in fractional shortening (14.6±1.6% versus 27.6±1.4% in wild type plus transverse aortic constriction mice; P<0.0001). Conversely, compensation of Carabin loss through a cardiotropic adeno-associated viral vector encoding Carabin prevented transverse aortic constrictioninduced cardiac hypertrophy with preserved fractional shortening (39.9±1.2% versus 25.9±2.6% in control plus transverse aortic constriction mice; P<0.0001). Carabin also conferred protection against adrenergic receptor-induced hypertrophy in isolated cardiomyocytes. Mechanistically, Carabin carries out a tripartite suppressive function. Indeed, Carabin, through its calcineurin-interacting site and Ras/Rab GTPase-activating protein domain, functions as an endogenous inhibitor of calcineurin and Ras/extracellular signal-regulated kinase prohypertrophic signaling. Moreover, Carabin reduced Ca 2+ / calmodulin-dependent protein kinase II activation and prevented nuclear export of histone deacetylase 4 after adrenergic stimulation or myocardial pressure overload. Finally, we showed that Carabin Ras-GTPase-activating protein domain and calcineurin-interacting domain were both involved in the antihypertrophic action of Carabin. Conclusions-Our study identifies Carabin as a negative regulator of key prohypertrophic signaling molecules, calcineurin, Ras, and Ca 2+/calmodulin-dependent protein kinase II and implicates Carabin in the development of cardiac hypertrophy and failure. (Circulation. 2015;131:390-400.

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“…37 Most recently, AAV-based vectors emerged as promising gene delivery vehicles. Based on the early promise of a small dose-finding study with an AAV1 vector expressing SERCA2a (CUPID), 38 a Phase 2b trial (CUPID2) was conducted but the results did not achieve the set endpoints, although no safety issues were observed.…”

Section: Anp Gene Deliverymentioning

confidence: 99%

Atrial Natriuretic Peptide　― Old But New Therapeutic in Cardiovascular Diseases ―

Ichiki¹,

Burnett²

2017

Circ J

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With the discovery of atrial natriuretic peptide (ANP), the heart as an endocrine organ was established. Basic science revealed that ANP, through the particulate guanylyl cyclase A receptor and cGMP, plays a fundamental role in cardiorenal biology. This work has led to the development of ANP as a therapeutic, especially in heart failure (HF). Human genomics has strengthened our understanding of ANP, revealing specific ANP gene variants that may be associated with biological dysfunction, but also may mediate protective properties, including in metabolic syndrome. Advances in understanding the processing and degradation of ANP molecular forms have resulted in therapeutic breakthroughs, especially inhibition of ANP degradation by neprilysin inhibitors. Although ANP is administered intravenously for acute HF, a novel therapeutic strategy is its chronic delivery by subcutaneous injection. An innovative therapeutic development is engineering to develop ANP-based peptides for chronic use. These interconnected topics of ANP biology and therapeutics will be reviewed in detail.

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Potential of gene therapy as a treatment for heart failure

Cited by 77 publications

References 86 publications

Effect of Allopurinol on Myocardial Energy Metabolism in Chronic Heart Failure Rats After Myocardial Infarct

Effect of Allopurinol on Myocardial Energy Metabolism in Chronic Heart Failure Rats After Myocardial Infarct

Carabin Protects Against Cardiac Hypertrophy by Blocking Calcineurin, Ras, and Ca ²⁺ /Calmodulin-Dependent Protein Kinase II Signaling

Atrial Natriuretic Peptide　― Old But New Therapeutic in Cardiovascular Diseases ―

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Potential of gene therapy as a treatment for heart failure

Cited by 77 publications

References 86 publications

Effect of Allopurinol on Myocardial Energy Metabolism in Chronic Heart Failure Rats After Myocardial Infarct

Effect of Allopurinol on Myocardial Energy Metabolism in Chronic Heart Failure Rats After Myocardial Infarct

Carabin Protects Against Cardiac Hypertrophy by Blocking Calcineurin, Ras, and Ca 2+ /Calmodulin-Dependent Protein Kinase II Signaling

Atrial Natriuretic Peptide ― Old But New Therapeutic in Cardiovascular Diseases ―

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Carabin Protects Against Cardiac Hypertrophy by Blocking Calcineurin, Ras, and Ca ²⁺ /Calmodulin-Dependent Protein Kinase II Signaling

Atrial Natriuretic Peptide　― Old But New Therapeutic in Cardiovascular Diseases ―