Unfolding the cardioprotective potential of sigma-1 receptor-directed molecular imaging

a Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany b Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama, Japan c Comprehensive Heart Failure Center, University Hospital Würzburg, Würzburg, Germany d The Russell H Morgan Department of Radiology and Radiological Sciences, Division of Nuclear Medicine and Molecular Imaging, Johns Hopkins School of Medicine, Baltimore, MD


See related article, pp. 653-661
As a chaperone crucially involved in protein folding, 1 Sigma-1 receptor (Sig-1R) has been extensively investigated in the context of neurogenerative disorders, such as Parkinson's or Alzheimer Disease. [1][2][3] In recent years, it has also gained interest within the cardiovascular community, as it exerts cardioprotective effects against a.) apoptosis, b.) hypertrophy and c.) maladjusted endoplasmic reticulum stress response. 1 In this regard, a Sig-1R in-vivo molecular imaging approach may not only provide further insights into cardiac ischemia post-myocardial infarction, 4 but also in the context of hypertrophy-related vascular injury. 1,5 In the present study, Wakabayashi and coworkers focused on myocardial ischemic burden and the targeting of Sig-1R using the SPECT probe I-125-iodophenyl-piperidinocyclopentanol (125I-OI5V). 6 Left coronary occlusion (LCA) was conducted over varying time frames of 10 to 30 min, followed by release of the snare, thereby allowing for reperfusion. 125I-OI5V increased depending on the ischemia time. Second, triple-radiotracer autoradiography including the myocardial perfusion probes 99mTc-MIBI and 201TI revealed that 125I-OI5V uptake ratio was negatively associated with 201TI uptake ratio, supporting the notion that the observed 125I-OI5V accumulation in areas of risk is not only related to the time of LCA, but also depending on reduced 201TI uptake. As such, SIG-1R expression may provide a read-out of the severity of ischemic burden. In addition, 125I-OIV uptake was also mainly located in and adjacent to (CD68-positive) areas of macrophage infiltration. 6 Although the herein used triple-tracer autoradiography approach is challenging and crucial for understanding the underlying uptake mechanism, the authors may have also provided further evidence on the feasibility of in-vivo imaging, as they have previously demonstrated in an ischemia-reperfusion model limited to 30 min using the identical radiotracer. 4 Second, the most recent work of Wakabayashi et al. published in this journal would have benefit from a more relevant clinical scenario. 6 For instance, in transient coronary occlusion models in rats, treatment with the selective Sig-1R agonist, 2-4-morpholinoethyl -1-phenylcyclohexane-1-carboxylate hydrochloride (PRE-084) led to improvement in cardiac outcome parameters, such as ejection fraction. 7 As such, future studies may also consider an image-guided treatment approach. 8 In this regard, rats could be treated with this Sig-1R antagonist at the time of maximum of target expression as provided by in-vivo 125I-OI5V SPECT and compared to off-peak treated animals, as it has been recently demonstrated for C-X-C motif chemokine receptor-targeted molecular imaging in murine studies. 9 Such an image-guided treatment would then link the herein observed 125I-OI5V uptake in damaged myocardium to a clinical meaning, in particular as the identical target would be used for both imaging and therapy. Such an assessment of the retention capacities prior to treatment on-set using Sig-1R antagonist would then resemble the widely adopted theranostic concept in nuclear oncology. 10,11 Nonetheless, the present work by Wakabayashi et al. is of importance, 6 as it provides the first step towards such an outcome-oriented experimental set-up.
Beyond its use for ischemic burden, other cardiovascular applications would be of even greater interest. As alluded to earlier, the role of Sig-1R in the context of hypertrophy has been already investigated. 5 In this regard, the vasculo-protective effect of Sig-1R on pressure overload hypertrophy-induced damage in the thoracic aorta has been already demonstrated by using Wistar rats, 5 i.e., the identical species that had also been used by Wakabyashi et al. in the present study. 6 In a sophisticated animal model of vascular injury caused by pressure overload, the Sig-1R agonist fluvoxamine led to restored pressure and protected against hypertrophy via upregulation of Sig1-R and stimulation of Sig-1R mediated Akt phosphorylation and endothelial nitric oxide synthase signaling. 5 Again, using 125I-OI5V in the context of pressure overload and hypertrophy, the Sig1-R retention capacities could be quantified, which may then allow to improve outcome in pressure overload-related vascular damage by initiating fluvoxamine treatment at the maximum of the SPECT signal. This would be even become more relevant if other Sig-1Rdirected antihypertensive drugs would be developed. 1 For instance, mice scheduled for transverse aortic constriction (TAC) could then be used and improvement of contractile function could then be investigated in animals treated at the maximum of 125I-OIV uptake. Of note, such TAC models have just been recently successfully investigated using the most commonly used PET radiotracer 18F-FDG. 12 Taken together, with its chaperone activity involved in protein folding, a direct in-vivo visualization of Sig1-R may be of interest in various clinical scenarios, in particular if Sig-1R drugs providing cardioprotective effects would become available. Until that, the beneficial impact of Sig-1R-targeted molecular imaging in the context of cardiovascular care may remain rather unfolded.

Funding
Open Access funding enabled and organized by Projekt DEAL. TH and RAW have been supported by the German Research Foundation (453989101; 507803309). TH has been supported by the Okayama University (RECTOR Program), and the Japan Society for the Promotion of Science (22H03027).

Disclosures
The authors declare that they have no conflict of interest.

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