Adrenergic receptors (ARs) are G protein-coupled receptors that are stimulated by catecholamines to induce a wide array of physiological effects across tissue types. Both a1and b-ARs are found on cardiomyocytes and regulate cardiac contractility and hypertrophy through diverse molecular pathways. Acute activation of cardiomyocyte b-ARs increases heart rate and contractility as an adaptive stress response. However, chronic b-AR stimulation contributes to the pathobiology of heart failure. By contrast, mounting evidence suggests that a1-ARs serve protective functions that may mitigate the deleterious effects of chronic b-AR activation.Here, we will review recent studies demonstrating that a1and b-ARs differentially regulate mitochondrial biogenesis and dynamics, mitochondrial calcium handling, and oxidative phosphorylation in cardiomyocytes. We will identify potential mechanisms of these actions and focus on the implications of these findings for the modulation of contractile function in the uninjured and failing heart. Collectively, we hope to elucidate important physiological processes through which these well-studied and clinically relevant receptors stimulate and fuel cardiac contraction to contribute to myocardial health and disease.
Trametinib (Trm) is a highly selective inhibitor of the tyrosine kinases MEK1/2 used to treat patients with melanoma and non-small cell lung cancer featuring BRAF mutations. Although Trm is generally well tolerated, it is associated with adverse cardiovascular effects including heart failure. Furthermore, the mechanisms underlying this cardiotoxicity are unclear. Here, we assessed the hypothesis that Trm decreases oxidative phosphorylation in the mouse heart. Female FVB mice were treated with Trm (3 mg/kg/d) or vehicle (DMSO) via oral gavage (n = 10, each group). We assessed cardiac contractility on Day 0 and Day 7 using echocardiography. We then performed electron transport chain (ETC) enzyme assays in isolated cardiac mitochondria and RNA sequencing of cardiac tissue to assess ETC Complex I-IV enzyme activity and ETC transcript abundance, respectively. Additionally, we measured citrate synthase (CS) activity as a marker for mitochondrial abundance. Mice treated with Trm had decreased fractional shortening on Day 7 compared to Day 0 (Panel A, 47.7 ± 1.6% vs. 55.5 ± 0.8%, p < 0.001) (mean ± SEM), confirming the cardiotoxicity of our treatment model. Additionally, mice treated with Trm had increased lung weight to heart weight (LW/HW) ratios compared to vehicle controls (Panel B, 1.69 ± 0.11 vs. 1.39 ± 0.03, p = 0.01), indicating heart failure. Mice treated with Trm had decreased CS (7,235 ± 586 vs. 8,562 ± 192 nmol/mg/min, p = 0.024), Complex II (1,659 ± 207 vs. 2,239 ± 239, p = 0.04), and Complex IV (3,979 ± 460 vs. 5,576 ± 615, p = 0.03) activities with a trend towards decreased Complex III (2,703 ± 452 vs. 3,554 ± 434, p = 0.09) activity (Panel C). Mice treated with Trm had decreased transcript abundance of Complex I (41 of 43), Complex II (6 of 6), Complex III (8 of 8), and Complex IV (18 of 23) transcripts (Panel D). Gene Ontology cellular compartment analysis of transcriptomic data revealed that Trm treatment primarily alters abundance of transcripts related to the mitochondrion (Panel E, p adj = 3.2 x 10 -113 ). KEGG Pathway analysis revealed that oxidative phosphorylation was the most significantly altered process following Trm treatment (Panel F, p adj = 2.9 x 10 -27 ). Collectively, these findings suggest that Trm causes widespread decreases in ETC activity that may hinder cardiomyocyte oxidative phosphorylation and contractility.
Aims: The sympathetic nervous system regulates numerous 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 endogenous ligands. The mechanisms through which α1A-ARs exert their cardioprotective effects remain unclear. Here we tested the hypothesis that α1A-ARs adaptively regulate cardiomyocyte oxidative metabolism in the uninjured and infarcted heart. Methods: We used an α1A-AR knockout mouse (α1A-KO) to characterize the effects of α1A-AR genetic deletion on mitochondrial function and metabolism in the uninjured mouse heart using high resolution respirometry, substrate-specific electron transport chain (ETC) enzyme assays, transmission electron microscopy (TEM) and proteomics. We then compared the effects of α1A- and β-AR agonist treatment on mitochondrial function in uninjured mice and mice subjected to experimental myocardial infarction. Results: We found that isolated cardiac mitochondria from α1A-KO mice had deficits in fatty acid-dependent respiration and ETC enzyme activity. TEM revealed abnormalities of mitochondrial morphology characteristic of these functional deficits. The selective α1A-AR agonist A61603 enhanced oxidative metabolism 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. 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.
Activation of alpha-1-adrenergic receptors (α1-ARs), particularly the a1A subtype, protects the murine heart against injury, whereas human studies show that a1-AR antagonists (α1-blockers) may increase the risk of heart failure. We created a cardiomyocyte-specific α1A-AR knockout mouse (cmAKO) to define the mechanisms underlying these effects and to elucidate whether they arise from cardiomyocyte α1A-ARs or systemic factors. Myocardial infarction (MI) resulted in 70% 7-day mortality in cmAKO compared to 10% in wild type (WT) mice. cmAKO mice exhibited exaggerated ventricular remodeling and increased cell death compared to WT mice 3 days post-MI, coupled to upregulation of canonical mediators of necroptosis: receptor-interacting protein (RIP) kinases RIP1 and RIP3 and mixed lineage kinase domain-like protein. An α1A-AR agonist mitigated ischemia-induced cardiomyocyte death and necroptotic signaling in vitro. A RIP1 antagonist abrogated the protective effects of α1A activation in vivo and in vitro. We found that patients at our center who were taking α-blockers at the time of MI experienced a higher risk of mortality (hazard ratio 1.53, p=0.029) during 5-year follow-up, providing clinical correlation for our experimental data. Collectively our findings indicate that cardiomyocyte α1A-ARs constrain ischemia-induced necroptosis and suggest caution in the use of α-blockers in patients at risk for MI.
Decreased electron transport chain (ETC) activity in cardiac mitochondria is a hallmark of heart failure. Gain- and loss-of-function studies define the benefits of alpha-1A adrenergic receptor (α1A-AR) activation in the failing heart, such as increased cardiac contractility. However, the mechanisms behind these effects are unknown, and α1A-AR activation as a method of ETC regulation has not been studied. Here, we assessed the hypotheses that decreased α1A-AR activation reduces ETC enzyme activity, whereas increased α1A-AR activation enhances ETC enzyme activity. We profiled citrate synthase and ETC complex I-IV activities in isolated cardiac mitochondria from (1) wild-type (WT) CL57Bl/6J mice or global α1A-AR knockout mice (10-12 wks) and (2) WT mice (10-12 wks) treated with vehicle (0.9% saline) or the selective α1A-AR agonist A61603 (10 ng/kg/d, 3 d). Citrate synthase, a key enzyme in the citric acid cycle, fuels ETC activity and is a commonly used marker for mitochondrial mass. Global α1A-AR knockout increased citrate synthase activity in male mice compared to WT controls (5,292 ± 275 vs. 4,198 ± 339 nmol/min/mg, n = 5 each group, p = 0.04) (mean ± SEM) (Panel A). When normalized to citrate synthase activity, global α1A-AR knockout decreased complex I (37 ± 10% vs. 64 ± 5%, p = 0.02) (1,786 ± 421 vs. 2,766 ± 422 nmol/min/mg) and complex II (25 ± 9% vs. 50 ± 13%, p = 0.01) (1,332 ± 219 vs. 2,032 ± 213 nmol/min/mg) activities with a trend toward decreased complex IV activity (33 ± 13% vs. 49 ± 17%, p = 0.07) (1,707 ± 201 vs. 2,000 ± 238 nmol/min/mg) (Panel B). A61603 treatment led to a trend towards decreased citrate synthase activity in female mice compared to vehicle controls (6,662 ± 501 vs. 7,701 ± 421 nmol/min/mg, n = 3 each group, p = 0.09) (Panel C). When normalized to citrate synthase activity, A61603 increased complex I (27 ± 3% vs. 17 ± 2%, p = 0.03) (1,736 ± 92 vs. 1,326 ± 156 nmol/min/mg), complex III (61 ± 6% vs. 37 ± 5%, p = 0.02) (3,993 ± 258 vs. 2,894 ± 531 nmol/min/mg), and complex IV (70 ± 6% vs. 48 ± 6%, p = 0.03) (4,631 ± 100 vs. 3,676 ± 533 nmol/min/mg) activities (Panel D). In conclusion, we show that global α1A-AR knockout decreases ETC enzyme activity, while treatment with an α1A-AR agonist increases ETC enzyme activity. These findings may identify a novel mechanism through which α1A-AR activation protects the injured and failing heart.
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