An Oral Selective Alpha-1A Adrenergic Receptor Agonist Prevents Doxorubicin Cardiotoxicity.
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ABSTRACT:
SUBMITTER: Beak J
PROVIDER: S-EPMC5343290 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:RATIONALE:Gq signaling in cardiac myocytes is classically considered toxic. Targeting Gq directly to test this is problematic, because cardiac myocytes have many Gq-coupled receptors. OBJECTIVE:Test whether Gq coupling is required for the cardioprotective effects of an alpha-1A-AR (adrenergic receptor) agonist. METHODS AND RESULTS:In recombinant cells, a mouse alpha-1A-AR with a 6-residue substitution in the third intracellular loop does not couple to Gq signaling. Here we studied a knockin mouse with this alpha-1A-AR mutation. Heart alpha-1A receptor levels and antagonist affinity in the knockin were identical to wild-type. In wild-type cardiac myocytes, the selective alpha-1A agonist A61603-stimulated phosphoinositide-phospholipase C and myocyte contraction. In myocytes with the alpha-1A knockin, both A61603 effects were absent, indicating that Gq coupling was absent. Surprisingly, A61603 activation of cardioprotective ERK (extracellular signal-regulated kinase) was markedly impaired in the KI mutant myocytes, and A61603 did not protect mutant myocytes from doxorubicin toxicity in vitro. Similarly, mice with the ?1A KI mutation had increased mortality after transverse aortic constriction, and A61603 did not rescue cardiac function in mice with the Gq coupling-defective alpha-1A receptor. CONCLUSIONS:Gq coupling is required for cardioprotection by an alpha-1A-AR agonist. Gq signaling can be adaptive.
| S-EPMC6742539 | biostudies-literature
Project description:Alpha-1-adrenergic receptors (?1-ARs) are G-protein coupled receptors (GPCRs) with three highly homologous subtypes (?1A, ?1B, and ?1D). Of these three subtypes, only the ?1A and ?1B are expressed in the heart. Multiple pre-clinical models of heart injury demonstrate cardioprotective roles for the ?1A. Non-selective ?1-AR activation promotes glycolysis in the heart, but the functional ?1-AR subtype and broader metabolic effects have not been studied.Given the high metabolic demands of the heart and previous evidence indicating benefit from ?1A activation, we chose to investigate the effects of ?1A activation on the cardiac metabolome in vivo.Mice were treated for one week with a low, subpressor dose of A61603, a highly selective and potent ?1A agonist. Cardiac tissue and serum were analyzed using a non-targeted metabolomics approach.We identified previously unrecognized metabolic responses to ?1A activation, most notably broad reduction in the abundance of polyunsaturated fatty acids (PUFAs) and endocannabinoids (ECs).Given the well characterized roles of PUFAs and ECs in inflammatory pathways, these findings suggest a possible role for cardiac ?1A-ARs in the regulation of inflammation and may offer novel insight into the mechanisms underlying the cardioprotective benefit of selective pharmacologic ?1A activation.
| S-EPMC5437747 | biostudies-literature
Project description:Doxorubicin is a widely used chemotherapeutic agent that causes dose-dependent cardiotoxicity in a subset of treated patients, but the genetic determinants of this susceptibility are poorly understood. Here, we report that a noncanonical tumor suppressor activity of p53 prevents cardiac dysfunction in a mouse model induced by doxorubicin administered in divided low doses as in the clinics. While relatively preserved in wild-type (p53 +/+ ) state, mice deficient in p53 (p53 -/- ) developed left ventricular (LV) systolic dysfunction after doxorubicin treatment. This functional decline in p53 -/- mice was associated with decreases in cardiac oxidative metabolism, mitochondrial mass, and mitochondrial genomic DNA (mtDNA) homeostasis. Notably, mice with homozygous knockin of the p53 R172H (p53 172H/H ) mutation, which like p53 -/- state lacks the prototypical tumor suppressor activities of p53 such as apoptosis but retains its mitochondrial biogenesis capacity, showed preservation of LV function and mitochondria after doxorubicin treatment. In contrast to p53-null state, wild-type and mutant p53 displayed distinct mechanisms of transactivating mitochondrial transcription factor A (TFAM) and p53-inducible ribonucleotide reductase 2 (p53R2), which are involved in mtDNA transcription and maintenance. Importantly, supplementing mice with a precursor of NAD+ prevented the mtDNA depletion and cardiac dysfunction. These findings suggest that loss of mtDNA contributes to cardiomyopathy pathogenesis induced by doxorubicin administered on a schedule simulating that in the clinics. Given a similar mtDNA protection role of p53 in doxorubicin-treated human induced pluripotent stem cell (iPSC)-derived cardiomyocytes, the mitochondrial markers associated with cardiomyopathy development observed in blood and skeletal muscle cells may have prognostic utility.
| S-EPMC6765288 | biostudies-literature
Project description:Improved therapy of cancer has significantly increased the lifespan of patients. However, cancer survivors face an increased risk of cardiovascular complications due to adverse effects of cancer therapies. The chemotherapy drug doxorubicin is well known to induce myofibril damage and cardiac atrophy. Our aim was to test potential counteracting effects of the pro-hypertrophic miR-212/132 family in doxorubicin-induced cardiotoxicity. In vitro, overexpression of the pro-hypertrophic miR-212/132 cluster in primary rodent and human iPSC-derived cardiomyocytes inhibited doxorubicin-induced toxicity. Next, a disease model of doxorubicin-induced cardiotoxicity was established in male C57BL/6N mice. Mice were administered either adeno-associated virus (AAV)9-control or AAV9-miR-212/132 to achieve myocardial overexpression of the miR-212/132 cluster. AAV9-mediated overexpression limited cardiac atrophy by increasing left ventricular mass and wall thickness, decreased doxorubicin-mediated apoptosis, and prevented myofibril damage. Based on a transcriptomic profiling we identified fat storage-inducing transmembrane protein 2 (Fitm2) as a novel target and downstream effector molecule responsible, at least in part, for the observed miR-212/132 anti-cardiotoxic effects. Overexpression of Fitm2 partially reversed the effects of miR-212/132. Overexpression of the miR-212/132 family reduces development of doxorubicin-induced cardiotoxicity and thus could be a therapeutic entry point to limit doxorubicin-mediated adverse cardiac effects.
| S-EPMC6319305 | biostudies-literature
Project description:BackgroundTranslation of preclinical findings could benefit from a simple, reproducible, high throughput human model to study myocardial signaling. Alpha-1A-adrenergic receptors (ARs) are expressed at very low levels in the human heart, and it is unknown if they function.ObjectivesTo develop a high throughput human myocardial slice culture model, and to test the hypothesis that alpha-1A- ARs are functional in the human heart.MethodsCores of LV free wall 8 mm diameter were taken from 52 hearts (18 failing and 34 nonfailing). Slices 250 μm thick were cut with a Krumdieck apparatus and cultured using a rotating incubation unit.ResultsAbout 60 slices were cut from each LV core, and a typical study could use 96 slices. Myocyte morphology was maintained, and diffusion into the slice center was rapid. Slice viability was stable for at least 3 days in culture by ATP and MTT assays. The beta-AR agonist isoproterenol stimulated phospholamban phosphorylation, and the alpha-1A-AR agonist A61603 stimulated ERK phosphorylation, with nanomolar EC50 values in slices from both failing and nonfailing hearts. Strips cut from the slices were used to quantify activation of contraction by isoproterenol, A61603, and phenylephrine. The slices supported transduction by adenovirus.ConclusionsWe have developed a simple, high throughput LV myocardial slice culture model to study signaling in the human heart. This model can be useful for translational studies, and we show for the first time that the alpha-1A-AR is functional in signaling and contraction in the human heart.
| S-EPMC4955869 | biostudies-literature
Project description:alpha 1-adrenergic receptors (ARs) play a major role in blood pressure regulation. The three alpha 1-AR subtypes (A/C, B, and D) stimulate contraction of isolated arteries, but it is uncertain how different subtypes contribute to blood pressure regulation in the intact animal. We studied the role of the alpha 1A/C subtype by using gene knockout. alpha 1A/C knockout (KO) mice were viable and overtly normal. The LacZ reporter gene replaced alpha 1A/C coding sequence in the KO, and beta-galactosidase staining was present in resistance arteries and arterioles, but not in the thoracic aorta or its main branches. By tail cuff manometer and arterial catheter in conscious mice, alpha 1A/C KO mice were hypotensive at rest, with an 8-12% reduction of blood pressure dependent on alpha 1A/C gene copy number. A61603, an alpha 1A/C-selective agonist, caused a pressor response that was lost in the KO and reduced but significant in heterozygous mice with a single copy of the alpha 1A/C. A subtype-nonselective agonist [phenylephrine (PE)] caused a pressor response in KO mice, but the final arterial pressure was only 85% of wild type. The baroreflex was reset in the KO, and heart rate variability was decreased. After baroreflex blockade with atropine, PE increased blood pressure but did not change heart rate. Cardiac and vascular responses to the beta-AR agonist isoproterenol were unchanged, and the arterial lumen area was not altered. We conclude that the alpha 1A/C-AR subtype is a vasopressor expressed in resistance arteries and is required for normal arterial blood pressure regulation. alpha 1A/C-selective antagonists might be desirable antihypertensive agents.
| S-EPMC123165 | biostudies-literature
Project description:OBJECTIVE:The anti-cancer anthracycline drug Doxorubicin (Dox) causes cardiotoxicity. We investigated the role of protease-activated receptor 1 (PAR-1) in Dox-induced cardiotoxicity. METHODS AND RESULTS:In vitro experiments revealed that PAR-1 enhanced Dox-induced mitochondrial dysfunction, reactive oxygen species and cell death of cardiac myocytes and cardiac fibroblasts. The contribution of PAR-1 to Dox-induced cardiotoxicity was investigated by subjecting PAR-1-/- mice and PAR-1+/+ mice to acute and chronic exposure to Dox. Heart function was measured by echocardiography. PAR-1-/- mice exhibited significant less cardiac injury and dysfunction compared to PAR-1+/+ mice after acute and chronic Dox administration. PAR-1-/- mice had reduced levels of nitrotyrosine, apoptosis and inflammation in their heart compared to PAR-1+/+ mice. Furthermore, inhibition of PAR-1 in wild-type mice with vorapaxar significantly reduced the acute Dox-induced cardiotoxicity. CONCLUSION:Our results indicate that activation of PAR-1 contributes to Dox-induced cardiotoxicity. Inhibition of PAR-1 may be a new approach to reduce Dox-induced cardiotoxicity in cancer patients.
| S-EPMC6173317 | biostudies-literature
Project description:Activation of beta3 adrenergic receptors on the surface of adipocytes leads to increases in intracellular cAMP and stimulation of lipolysis. In brown adipose tissue, this serves to up-regulate and activate the mitochondrial uncoupling protein 1, which mediates a proton conductance pathway that uncouples oxidative phosphorylation, leading to a net increase in energy expenditure. While chronic treatment with beta3 agonists in nonprimate species leads to uncoupling protein 1 up-regulation and weight loss, the relevance of this mechanism to energy metabolism in primates, which have much lower levels of brown adipose tissue, has been questioned. With the discovery of L-755,507, a potent and selective partial agonist for both human and rhesus beta3 receptors, we now demonstrate that acute exposure of rhesus monkeys to a beta3 agonist elicits lipolysis and metabolic rate elevation, and that chronic exposure increases uncoupling protein 1 expression in rhesus brown adipose tissue. These data suggest a role for beta3 agonists in the treatment of human obesity.
| S-EPMC508828 | biostudies-other
Project description:There is a need for treatments to reduce coronavirus disease 2019 (COVID-19) mortality. Alpha-2 adrenergic receptor (α2 AR) agonists can dampen immune cell and inflammatory responses as well as improve oxygenation through physiologic respiratory parameters. Therefore, α2 AR agonists may be effective in reducing mortality related to hyperinflammation and acute respiratory failure in COVID-19. Dexmedetomidine (DEX) is an α2 AR agonist used for sedation. We performed a retrospective analysis of adults at Rush University System for Health hospitals between March 1, 2020 and July 30, 2020 with COVID-19 requiring invasive mechanical ventilation and sedation (n = 214). We evaluated the association of DEX use and 28-day mortality from time of intubation. Overall, 28-day mortality in the cohort receiving DEX was 27.0% as compared to 64.5% in the cohort that did not receive DEX (relative risk reduction 58.2%; 95% CI 42.4-69.6). Use of DEX was associated with reduced 28-day mortality on multivariable Cox regression analysis (aHR 0.19; 95% CI 0.10-0.33; p < 0.001). Adjusting for time-varying exposure to DEX also demonstrated that DEX was associated with reduced 28-day mortality (aHR 0.51; 95% CI 0.28-0.95; p = 0.03). Earlier DEX use, initiated <3.4 days from intubation, was associated with reduced 28-day mortality (aHR 0.25; 95% CI 0.13-0.50; p < 0.001) while later DEX use was not (aHR 0.64; 95% CI 0.27-1.50; p = 0.30). These results suggest an α2 AR agonist might reduce mortality in patients with COVID-19. Randomized controlled trials are needed to confirm this observation.
| S-EPMC8764306 | biostudies-literature
Project description:In mammals, increasing evidence supports the generality of cotranscriptional gene regulation and the idea that genetic control often occurs subsequent to RNA polymerase II (Pol II) recruitment. In our recent experiments, we have used Pol II Chromatin Immunoprecipitation (ChIP) to investigate relationships between the mechanistic events that control acute stress response (ASR) gene activation following stimulation of the alpha1a-Adrenergic Receptor expressed in rat-1 fibroblasts. We validate the temporal accuracy of our Pol II ChIP assay by comparison to major transcriptional events assessable by microarray and PCR analysis of precursor and mature mRNA. Initial temporal microarray analysis of gene activation following agonist addition identified genes that were upregulated and provided a temporal profile of changes in polyadenylated mRNA levels. Combined with PCR analysis of pre-mRNA, total RNA, polyadenylated RNA and the Pol II ChIP data, we demonstrate complex multilevel gene regulation including a diverse set of cotranscriptional mechanisms. Given our data, we propose that analysis of a genes regulation must begin with global assessement of changes in transcriptional behavior to identify events that are actually rate limiting if reductionist mechanistic dissection is to distinguish events that are regulated from the larger set of mechanisms available to most genes. This microarray analysis reports on the temporal changes in polyadenylated mRNA levels in proliferating rat-1 fibroblasts following stimulation of the alpha-1a Adrenergic Receptor with filter sterilized 10 uM phenylephrine (PE). Cells were treated and harvested at 70 to 80% confluence. Rat-1 cells under these conditions are still mid-log phase and continue to proliferate for at least another replicative cycle. Message levels in untreated cells were determined for 3 biological replicates, but all other time points are single replicates as sufficiently detailed dissection made replicates expensive and unnecessary, given that clear trending behavior in the expression profiles demonstrates profile accuracy.
2014-08-01 | E-GEOD-59955 | biostudies-arrayexpress