An Oral Selective Alpha-1A Adrenergic Receptor Agonist Prevents Doxorubicin Cardiotoxicity

Beak, Ju Youn; Huang, Wei; Parker, Joel S.; Hicks, BS Sean T.; Patterson, Cam; Simpson, Paul C.; Ma, Anqi; Jin, Jian; Jensen, Brian C.

doi:10.1016/j.jacbts.2016.10.006

Cited by 44 publications

(42 citation statements)

References 50 publications

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“…6d and Supplementary Fig. 9F) 53 . These preserved cytosolic functions of ERK1/2 in cells transduced with EDI (vs. MEK inhibition) may be particularly relevant in patients with a second source of cardiac injury (e.g.…”

Section: Discussionmentioning

confidence: 96%

Interference with ERK-dimerization at the nucleocytosolic interface targets pathological ERK1/2 signaling without cardiotoxic side-effects

et al. 2020

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Dysregulation of extracellular signal-regulated kinases (ERK1/2) is linked to several diseases including heart failure, genetic syndromes and cancer. Inhibition of ERK1/2, however, can cause severe cardiac side-effects, precluding its wide therapeutic application. ERK T188autophosphorylation was identified to cause pathological cardiac hypertrophy. Here we report that interference with ERK-dimerization, a prerequisite for ERK T188 -phosphorylation, minimizes cardiac hypertrophy without inducing cardiac adverse effects: an ERK-dimerization inhibitory peptide (EDI) prevents ERK T188 -phosphorylation, nuclear ERK1/2-signaling and cardiomyocyte hypertrophy, protecting from pressure-overload-induced heart failure in mice whilst preserving ERK1/2-activity and cytosolic survival signaling. We also examine this alternative ERK1/2-targeting strategy in cancer: indeed, ERK T188 -phosphorylation is strongly upregulated in cancer and EDI efficiently suppresses cancer cell proliferation without causing cardiotoxicity. This powerful cardio-safe strategy of interfering with ERK-dimerization thus combats pathological ERK1/2-signaling in heart and cancer, and may potentially expand therapeutic options for ERK1/2-related diseases, such as heart failure and genetic syndromes.

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Section: Discussionmentioning

confidence: 96%

Interference with ERK-dimerization at the nucleocytosolic interface targets pathological ERK1/2 signaling without cardiotoxic side-effects

et al. 2020

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“…As an example, we find that a different α1A agonist protects cardiac mitochondria and ATP levels [31]. …”

Section: Discussionmentioning

confidence: 99%

An Alpha-1A Adrenergic Receptor Agonist Prevents Acute Doxorubicin Cardiomyopathy in Male Mice

et al. 2017

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Alpha-1 adrenergic receptors mediate adaptive effects in the heart and cardiac myocytes, and a myocyte survival pathway involving the alpha-1A receptor subtype and ERK activation exists in vitro. However, data in vivo are limited. Here we tested A61603 (N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide), a selective imidazoline agonist for the alpha-1A. A61603 was the most potent alpha-1-agonist in activating ERK in neonatal rat ventricular myocytes. A61603 activated ERK in adult mouse ventricular myocytes and protected the cells from death caused by the anthracycline doxorubicin. A low dose of A61603 (10 ng/kg/d) activated ERK in the mouse heart in vivo, but did not change blood pressure. In male mice, concurrent subcutaneous A61603 infusion at 10 ng/kg/d for 7 days after a single intraperitoneal dose of doxorubicin (25 mg/kg) increased survival, improved cardiac function, heart rate, and cardiac output by echocardiography, and reduced cardiac cell necrosis and apoptosis and myocardial fibrosis. All protective effects were lost in alpha-1A-knockout mice. In female mice, doxorubicin at doses higher than in males (35–40 mg/kg) caused less cardiac toxicity than in males. We conclude that the alpha-1A-selective agonist A61603, via the alpha-1A adrenergic receptor, prevents doxorubicin cardiomyopathy in male mice, supporting the theory that alpha-1A adrenergic receptor agonists have potential as novel heart failure therapies.

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“…Of particular interest is the evidence that a 1A -adrenoceptors are cardioprotective in heart failure. Activation of a 1 -adrenoceptors in the heart reduces pathologic remodelling, inhibits cell death, and improves myocyte contractility (Jensen et al, 2011;O'Connell et al, 2013;Willis et al, 2016;Beak et al, 2017) by mechanisms that include facilitation of glucose uptake (Tian and Abel, 2001;Shi et al, 2016). The role of a 1Aadrenoceptors in the failing heart is increasingly important for a number of reasons.…”

Section: A Adrenoceptorsmentioning

confidence: 99%

G Protein–Coupled Receptors Targeting Insulin Resistance, Obesity, and Type 2 Diabetes Mellitus

Riddy¹,

Delerive²,

Summers³

et al. 2017

Pharmacol Rev

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G protein-coupled receptors (GPCRs) continue to be important discovery targets for the treatment of type 2 diabetes mellitus (T2DM). Many GPCRs are directly involved in the development of insulin resistance and -cell dysfunction, and in the etiology of inflammation that can lead to obesity-induced T2DM. This review summarizes the current literature describing a number of well-validated GPCR targets, but also outlines several new and promising targets for drug discovery. We highlight the importance of understanding the role of these receptors in the disease pathology, and their basic pharmacology, which will pave the way to the development of novel pharmacological probes that will enable these targets to fulfill their promise for the treatment of these metabolic disorders.

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An Oral Selective Alpha-1A Adrenergic Receptor Agonist Prevents Doxorubicin Cardiotoxicity

Abstract: Visual Abstract

Cited by 44 publications

References 50 publications

Interference with ERK-dimerization at the nucleocytosolic interface targets pathological ERK1/2 signaling without cardiotoxic side-effects

Interference with ERK-dimerization at the nucleocytosolic interface targets pathological ERK1/2 signaling without cardiotoxic side-effects

An Alpha-1A Adrenergic Receptor Agonist Prevents Acute Doxorubicin Cardiomyopathy in Male Mice

G Protein–Coupled Receptors Targeting Insulin Resistance, Obesity, and Type 2 Diabetes Mellitus

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