DOI: 10.4231/mjjv-f581
title: The Alpha-1A Adrenergic Receptor Regulates Mitochondrial Oxidative Metabolism in the Mouse Heart

description: &lt;p&gt;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 &alpha;1-ARs, particularly the &alpha;1A subtype, are cardioprotective and may mitigate the deleterious effects of chronic &beta;-AR activation by shared ligands. The mechanisms underlying these adaptive effects remain unclear. Here, we tested the hypothesis that &alpha;1A-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 &alpha;1A-AR knockout mice and defined the effects of chronic &beta;-AR activation and myocardial infarction on selected mitochondrial functions.&lt;/p&gt;

&lt;p&gt;Results: We found that isolated cardiac mitochondria from &alpha;1A-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 &alpha;1A-AR agonist A61603 enhanced fatty-acid dependent respiration, fatty acid oxidation, and ETC enzyme activity in isolated cardiac mitochondria. The &beta;-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.&lt;/p&gt;

&lt;p&gt;Conclusions: Collectively, these novel findings position &alpha;1A-ARs as critical regulators of cardiomyocyte metabolism in the basal state and suggest that metabolic mechanisms may underlie the protective effects of &alpha;1A-AR activation in the failing heart.&lt;/p&gt;

&lt;p&gt;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 &alpha;1A-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)&lt;/p&gt;

&lt;p&gt; &lt;/p&gt;

&lt;p&gt;Sample Abbreviation: &lt;/p&gt;

&lt;p&gt;aAR1KO: global &alpha;1A-AR knockout mice&lt;/p&gt;

&lt;p aria-hidden="true"&gt;Sample list:&lt;/p&gt;

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 &lt;p&gt;control&lt;/p&gt;
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 &lt;td nowrap="nowrap" valign="bottom" width="81"&gt;
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 &lt;td nowrap="nowrap" width="79"&gt;
 &lt;p&gt;control&lt;/p&gt;
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 &lt;/tr&gt;
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 &lt;td nowrap="nowrap" width="79"&gt;
 &lt;p&gt;control&lt;/p&gt;
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 &lt;td nowrap="nowrap" valign="bottom" width="81"&gt;
 &lt;p align="center"&gt;&lt;b&gt;820&lt;/b&gt;&lt;/p&gt;
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 &lt;td nowrap="nowrap" valign="bottom" width="81"&gt;
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 &lt;td nowrap="nowrap" valign="bottom" width="81"&gt;
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 &lt;td nowrap="nowrap" width="79"&gt;
 &lt;p&gt;aAR1KO&lt;/p&gt;
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 &lt;td nowrap="nowrap" valign="bottom" width="81"&gt;
 &lt;p align="center"&gt;&lt;b&gt;829&lt;/b&gt;&lt;/p&gt;
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 &lt;/tbody&gt;
&lt;/table&gt;

&lt;p aria-hidden="true"&gt; &lt;/p&gt;

&lt;p aria-hidden="true"&gt; &lt;/p&gt;
description: Description of data: 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.