The Alpha-1A Adrenergic Receptor Regulates Mitochondrial Oxidative Metabolism in the Mouse Heart

<p>Aims: The sympathetic nervous system regulates numerous critical aspects of mitochondrial function in the heart through activation of adrenergic receptors (ARs) on cardiomyocytes. Mounting evidence suggests that α1-ARs, particularly the α1A subtype, are cardioprotective and may mitigate the deleterious effects of chronic β-AR activation by shared ligands. The mechanisms underlying these adaptive effects remain unclear. Here, we tested the hypothesis that α1A-ARs adaptively regulate cardiomyocyte oxidative metabolism in both the uninjured and infarcted heart.  Methods: We used high resolution respirometry, fatty acid oxidation (FAO) enzyme assays, substrate-specific electron transport chain (ETC) enzyme assays, metabolomics, transmission electron microscopy (TEM) and proteomics to characterize mitochondrial function comprehensively in the uninjured hearts of wild type and α1A-AR knockout mice and defined the effects of chronic β-AR activation and myocardial infarction on selected mitochondrial functions.</p>

<p>Results: We found that isolated cardiac mitochondria from α1A-KO mice had deficits in fatty acid-dependent respiration, FAO, and ETC enzyme activity. TEM revealed abnormalities of mitochondrial morphology characteristic of these functional deficits. The selective α1A-AR agonist A61603 enhanced fatty-acid dependent respiration, fatty acid oxidation, and ETC enzyme activity in isolated cardiac mitochondria. The β-AR agonist isoproterenol enhanced oxidative stress in vitro and this adverse effect was mitigated by A61603. A61603 enhanced ETC Complex I activity and protected contractile function following myocardial infarction.</p>

<p>Conclusions: Collectively, these novel findings position α1A-ARs as critical regulators of cardiomyocyte metabolism in the basal state and suggest that metabolic mechanisms may underlie the protective effects of α1A-AR activation in the failing heart.</p>

<p>Data Acquisition: Description of data: Files (.d) containing raw data of  abundance of long chain acylcarnitines, short and medium chain acylcarnitines, and metabolites in ventricular tissue determined via lipidomics from control and global α1A-AR knockout (aAR1KO) mice. The files have been generated using a Agilent 6410 triple quadrupole. The method of acquisition used was MRM profiling (1-2)</p>

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<p>Sample Abbreviation: </p>

<p>aAR1KO: global α1A-AR knockout mice</p>

<p aria-hidden="true">Sample list:</p>

<table border="0" cellpadding="0" cellspacing="0" width="160">
<tbody>
<tr>
<td nowrap="nowrap" width="79">
<p>control</p>
</td>
<td nowrap="nowrap" valign="bottom" width="81">
<p align="center"><b>817</b></p>
</td>
</tr>
<tr>
<td nowrap="nowrap" width="79">
<p>control</p>
</td>
<td nowrap="nowrap" valign="bottom" width="81">
<p align="center"><b>818</b></p>
</td>
</tr>
<tr>
<td nowrap="nowrap" width="79">
<p>control</p>
</td>
<td nowrap="nowrap" valign="bottom" width="81">
<p align="center"><b>819</b></p>
</td>
</tr>
<tr>
<td nowrap="nowrap" width="79">
<p>control</p>
</td>
<td nowrap="nowrap" valign="bottom" width="81">
<p align="center"><b>820</b></p>
</td>
</tr>
<tr>
<td nowrap="nowrap" width="79">
<p>control</p>
</td>
<td nowrap="nowrap" valign="bottom" width="81">
<p align="center"><b>821</b></p>
</td>
</tr>
<tr>
<td nowrap="nowrap" width="79">
<p>control</p>
</td>
<td nowrap="nowrap" valign="bottom" width="81">
<p align="center"><b>822</b></p>
</td>
</tr>
<tr>
<td nowrap="nowrap" width="79">
<p>aAR1KO</p>
</td>
<td nowrap="nowrap" valign="bottom" width="81">
<p align="center"><b>823</b></p>
</td>
</tr>
<tr>
<td nowrap="nowrap" width="79">
<p>aAR1KO</p>
</td>
<td nowrap="nowrap" valign="bottom" width="81">
<p align="center"><b>824</b></p>
</td>
</tr>
<tr>
<td nowrap="nowrap" width="79">
<p>aAR1KO</p>
</td>
<td nowrap="nowrap" valign="bottom" width="81">
<p align="center"><b>825</b></p>
</td>
</tr>
<tr>
<td nowrap="nowrap" width="79">
<p>aAR1KO</p>
</td>
<td nowrap="nowrap" valign="bottom" width="81">
<p align="center"><b>826</b></p>
</td>
</tr>
<tr>
<td nowrap="nowrap" width="79">
<p>aAR1KO</p>
</td>
<td nowrap="nowrap" valign="bottom" width="81">
<p align="center"><b>827</b></p>
</td>
</tr>
<tr>
<td nowrap="nowrap" width="79">
<p>aAR1KO</p>
</td>
<td nowrap="nowrap" valign="bottom" width="81">
<p align="center"><b>828</b></p>
</td>
</tr>
<tr>
<td nowrap="nowrap" width="79">
<p>aAR1KO</p>
</td>
<td nowrap="nowrap" valign="bottom" width="81">
<p align="center"><b>829</b></p>
</td>
</tr>
</tbody>
</table>

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