University of Groningen
Development of PET tracers for investigation of arginase-related pathways
dos Santos Clemente, Gonçalo
DOI:
10.33612/diss.143845684
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dos Santos Clemente, G. (2020). Development of PET tracers for investigation of arginase-related pathways. University of Groningen. https://doi.org/10.33612/diss.143845684
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Chapter 5
Abstract
Several research groups have suggested that part of the therapeutic success of statins, and also some of the pleiotropic effects associated with this class of drugs, are due to their impact on the arginase/nitric oxide synthase (NOS) signaling pathways. Although the proposed mechanisms of action are not always universally accepted, the undeniable capacity of statins to increase NO• levels has attracted
much research interest to expand their therapeutic spectrum. Therefore, the potential effects induced by statins in ʟ-arginine metabolic pathways are briefly reviewed.
Introduction
As reviewed in chapter 2, the balance between arginase isozymes (Arg1 and Arg2) and the endothelial, neuronal, and inducible nitric oxide synthase (e/n/iNOS) has shown to be highly linked to several pathophysiological processes. Besides a range of immune-mediated pathologies, arginase is particularly overexpressed in cardiovascular diseases [1]. The upregulation of the arginase levels leads to arterial stiffening, to the depletion of ʟ-arginine (the common substrate with NOS), and consequently to the reduction of NO•-mediated cardioprotective effects [2]. For
example, a high fat/cholesterol diet may cause liver damage, which contributes to the systemic release of the hepatic cytosolic arginase and worsens further hypercholesterolemia-induced vascular dysfunction [3]. Therefore, several reports have suggested that part of the therapeutic success of statins, the most prescribed cholesterol-lowering drugs for the prevention of atherosclerotic diseases, may be related to off-target effects influencing arginase/NOS signaling pathways, in parallel to the primary HMG-CoA (3-hydroxy-3-methyl-glutaryl-coenzyme A) reductase inhibition [4].
Statins as HMG-CoA reductase inhibitors
HMG-CoA reductase is an intermediate enzyme of the mevalonate pathway, involved in the biosynthesis of cholesterol. Although this enzyme is widely expressed throughout most tissues [5], the liver is central to the balancing of cholesterol levels in the body by regulating its synthesis, transport, and elimination through bile. Thus, the inhibition of HMG-CoA reductase became an essential clinical strategy for the treatment of hypercholesterolemia, which is currently one of the lead risk factors for heart disease and stroke [6].
From the early 1970s on, when mevastatin was first isolated from Penicillium citrinum and was screened as being a potent HMG-CoA reductase inhibitor, numerous other statins have been isolated from fungi or chemically synthesized [7]. Some of these statins revealed high affinity and specificity to inhibit HMG-CoA reductase and reached clinical trials, being later added, and occasionally even withdrawn (due to adverse effects), from medical prescription (Figure 1) [8].
Figure 1. Chemical structure of mevastatin and natural, semi-synthetic, and synthetic statins currently approved for clinical use.
Statins efficiently reduce the synthesis of endogenous cholesterol by mimicking and outcompeting HMG-CoA, the HMG-CoA reductase natural substrate (Figure 2) [9]. This selective inhibition of HMG-CoA reductase triggers the activity of hepatic LDL (low-density lipoprotein) receptors, lowering plasma LDL cholesterol concentration, which is causally linked to the risk of cardiovascular events, while modestly increasing levels of the beneficial HDL (high-density lipoprotein)
cholesterol [10]. The high therapeutic effect of statins, and their relevance for the primary and secondary prevention of atherosclerotic cardiovascular diseases, made this class of drugs the most successful of all-time, with a global market value of tens of billions of dollars per year [11].
Figure 2. Cholesterol biosynthetic pathway and inhibition of HMG-CoA reductase by statins that leads to decreased levels of cholesterol and small guanosine triphosphatases (Ras, Rho, Rac1).
Pleiotropic effects of statins
In addition to the unambiguous cholesterol-lowering action, the success of statins became increasingly connected with broader pleiotropic effects [12]. More and more often, statins are being associated with potential protective effects on pathologies beyond cardiovascular diseases (e.g., respiratory [13], carcinogenic [14], viral [15], and neurodegenerative [16]), which may expand their therapeutic spectrum.
As depicted in Figure 2, the mevalonate pathway leads to pyrophosphate intermediates that are necessary for the biosynthesis of cholesterol and small guanosine triphosphatases (Ras, Rho, and Rac1) important in intracellular signal transduction. Multiple processes, such as cell migration, proliferation, or apoptosis, depend on the downstream products of mevalonate [17]. The decrease in the systemic levels of those pyrophosphate intermediates due to HMG-CoA reductase
inhibition is expected to reduce the signals from Ras, Rho, and Rac1, which may explain many of statins pleiotropic effects (e.g., antioxidant, anti-inflammatory, anti-proliferative, and immunomodulatory effects [18]), including a potential reduction of arginase activity and increase of NO• levels [19].
Arginase/NOS regulation by statins
Several in vitro and in vivo studies have confirmed the capacity of statins to suppress arginase activity and/or increase the NO• levels (Table 1).
Table 1. Statin-induced effects on the arginase/NOS signaling pathways and suggested mechanisms.
Research model Statin Output Ref
Bovine aortic endothelial cells Atorvastatin
caveolin-1 expression eNOS expression NO•
[4c]
Bovine aortic endothelial cells Simvastatin
eNOS mRNA expression eNOS expression NO•
[4k]
Bovine aortic endothelial cells Simvastatin Rosuvastatin
↑ eNOS mRNA stability ↑ eNOS expression NO•
[20]
Human aortic endothelial cells Lovastatin
Simvastatin Rho
arginase activity [19]
Human umbilical vein endothelial cells Cerivastatin
GTPCH mRNA BH4 levels
eNOS activity NO•
[21]
Human umbilical vein endothelial cells Pitavastatin
Akt phosphorylation eNOS activity NO•
[4e]
Human umbilical vein endothelial cells Pitavastatin Cerivastatin
Akt phosphorylation eNOS activity NO•
[4g]
Human umbilical vein endothelial cells Fluvastatin Cerivastatin ↑ eNOS mRNA ↑ BH4 levels ↑ GTPCH mRNA Akt phosphorylation NO• [22]
Human umbilical vein endothelial cells Healthy mice
Atorvastatin Lovastatin
↑ AMPK
↑ eNOS [23]
Human umbilical vein and mouse cardiac
microvascular endothelial cells Atorvastatin
caveolin-1 expression eNOS expression NO•
Research model Statin Output Ref
MCF-7 breast cancer cells Fluvastatin
Simvastatin iNOS mRNA iNOS expression NO• cell proliferation [25]
MCF-7 breast cancer cells Atorvastatin PI3K signaling through Akt cell growth suppression [26]
Healthy mice Rosuvastatin
caveolin-1 expression eNOS expression NO•
[27]
Normocholesterolemic mice Atorvastatin
Rho
↑ eNOS expression NO•
neuroprotection effect
[28]
Mouse model of allergic asthma Simvastatin goblet cell hyperplasia arginase expression [29]
Erchlich acid (breast cancer) xenograft mice Rosuvastatin
arginase activity ornithine levels polyamines levels NO•
[30]
Diabetic mice Pitavastatin
eNOS uncoupling GTPCH mRNA expression eNOS uncoupling NO•
[31]
Diabetic rats Simvastatin
Rho
eNOS expression NO•
endothelial function
[32]
Diabetic rats Simvastatin Rho
arginase activity [33]
Cirrhotic rats Atorvastatin
Rho
↑ eNOS expression NO•
[34]
Cirrhotic rats Simvastatin
Akt phosphorylation eNOS activity NO•
[35]
Rats with hypoxia-induced pulmonary
hypertension Fluvastatin
eNOS mRNA expression endothelin synthesis/secretion NO•
lung function
[36]
Hypercholesterolemic rabbits Simvastatin
eNOS mRNA expression eNOS expression O2
•- NO•
[4b]
Clinical trials in hypercholesterolemic
humans Atorvastatin arginase activity BH4 levels eNOS uncoupling NO• [4i, 4j, 37]
Within the scope of this chapter, assays were performed to evaluate the capacity of statins to bind and inhibit arginase. Using a label-free surface plasmon resonance ResidenceTimer™ assay developed by NTRC (Oss, The Netherlands) in a BiaCore T200 (GE Healthcare), with Arg1 (diluted in 50 mM Na2HPO4, pH 7.4, 150 mM KCl,
and 0.01% Tween-20, in a concentration of 60 μg/mL) immobilized on a sensor chip and five concentrations (between 0.1-10 µM) of a reference arginase inhibitor (2-(S)-amino-6-boronohexanoic acid) and atorvastatin, it was confirmed that atorvastatin does not inhibit or bind to arginase [unpublished data]. Therefore, HMG-CoA reductase inhibition (on-target) downstream routes and other apparently off-target mechanisms have been proposed in the literature to explain the statin-induced increase of NO• levels (Figure 3).
Figure 3. Schematic summary of the main pathways involved in the capacity of statins to suppress arginase activity and/or increase the NO• levels.
As mentioned above, statins inhibit HMG-CoA reductase by suppressing the downstream products of mevalonate, including the Rho small guanosine triphosphatase. By decreasing the availability of Rho effectors (Figure 3, pathway 1), which negatively influence eNOS mRNA stability and activity by inducing the cleavage of the poly(A) signal sequence, statins showed to increase the subsequent translation to eNOS [18c, 20]. Rho effectors also can inhibit protein kinase B (Akt), an enzyme that, together with the phosphatidylinositol-3 kinase
(PI3K), is essential for the phosphorylation and activation of eNOS [4e, 4g]. Thus, by suppressing the Rho-induced inhibition of PI3K/Akt, statins are contributing to the increase of eNOS activity. Furthermore, a specific Rho effector (mDial1) seems to be responsible for the liberation of mitochondrial Arg2, leading to arginase upregulation and depletion of ʟ-arginine. The inhibition of mDial1 by statins is also thought to be one of the mechanisms that lead to NO• increase [19].
Another way how statins may affect the phosphorylation of eNOS seems to be via activation of AMPK (adenosine monophosphate-activated protein kinase, Figure 3, pathway 2). This activation of AMPK has been shown to increase NO• production
either in vitro or in vivo, but there are still uncertainties whether or not this mechanism is directly dependent on the inhibition of the mevalonate pathway [23]. The pretreatment of endothelial cells with statins showed to decrease caveolin-1 levels (Figure 3, pathway 3) [4c, 24, 38]. Caveolin-1 is a component of plasma membranes that is usually co-localized with eNOS and can inactivate this enzyme by blocking its essential interaction with the Ca2+/calmodulin cofactor [39].
Statins seem to exert some epigenetic modifications (Figure 3, pathway 4 and 5), but the exact mechanisms of action and target regions remain unclear [4m]. Measurement of the guanosine triphosphate cyclohydrolase I (GTPCH) mRNA levels by real-time polymerase chain reaction (PCR) in vascular endothelial cells pretreated with statins showed an enhancement of this mRNA [21, 31]. GTPCH is a rate-limiting enzyme for the synthesis of tetrahydrobiopterin (BH4), which is an
essential cofactor for eNOS coupling and function. It is noteworthy that uncoupled eNOS leads to the production of O2•− parallelly to NO•, forming cytotoxic
peroxynitrite species (ONOO−). Additionally, in vitro studies with statins showed a
reduction in the expression of micro RNAs that negatively impact eNOS expression, which led to an increase of NO• release [40].
Even though some proposed mechanisms are still controversial, it is undeniable that statins increase eNOS activity and NO• levels. The production of NO• involves
the synthesis of an intermediate molecule by NOS, Nω-hydroxy-ʟ-arginine (NOHA),
that is known to exert an inhibitory effect on arginase [41], which may also be an indirect way of how statins can inhibit arginase [4i, 29].
Discussion
Although the reported experimental data on the pleiotropic effects of statins are strongly suggestive and triggered a growing interest in the use of statins beyond
cardiovascular diseases [12b], there has been limited evidence of the potential benefits in humans. The long-term knowledge of some adverse effects of statins (e.g., muscle pain, digestive problems, mental fuzziness, or hepatotoxicity), and the reports of some intolerant or resistant patients, might have delayed the stimulation of further clinical trials. However, the confirmation that statins could influence the arginase–NO• network (Table 1), and the recent emergence of this enzymatic
system as a potential therapeutic target [1], led to the resurgence of the interest to use statins as an innovative or complementary therapy, especially for carcinogenic, neurodegenerative, and airway diseases [42].
Despite the fact that randomized controlled trials showed no benefits on the use of statins in patients with advanced cancer and, therefore, poor prognosis [43], epidemiological studies have associated the use of statins with lower breast and colorectal cancer risk in humans [44]. Patients with neurodegenerative and cognitive disorders treated with statins have also shown inconsistent results, as both an aggravation and an improvement in symptoms have been reported [45]. More consistent results have been achieved regarding the benefits of using statins in chronic obstructive pulmonary diseases and asthma [46], two airway inflammation disorders that recently showed to potentially benefit from the treatment with arginase inhibitors due to the increase of NO• levels and
concomitant decrease of polyamines [47]. Highly lipophilic statins, such as atorvastatin, apparently have a greater propensity to cause pleiotropic effects [26, 48] as they easily diffuse across cell plasma membranes achieving a broader biodistribution and, therefore, are more likely to reach off-target regions [49]. Nevertheless, this lipophilicity may also be the reason why off-target effects are less visible in vivo than in vitro [50], as statins are subject to an extensive liver (primary target) first-pass retention [51]. Thus, to bypass hepatic retention and increase the bioavailability to other regions, the development of injectable and inhaled formulations of statins have sparked clinical interest [52]. Recently, a first step towards the evaluation of inhaled statins has been taken with the safety testing in non-human primates, which revealed good tolerance to the nebulization in the airways without evidence of adverse injuries [53].
Many in vitro and in vivo studies have shown promising benefits for using statins beyond cardiovascular diseases, but the still scarce translations to human trials have mostly failed to replicate the same results consistently. Furthermore, additional studies are needed to confirm the relevance of the pathways involved in the capacity of statins to suppress arginase activity and/or increase the NO• levels
bioavailability, type of statin, treatment duration, or on the sensitivity of the model used.
Conclusion
The pleiotropic effects of statins have been the subject of scientific and clinical interest for several years. These effects are still controversial as their outcomes are not always observed or significant when translated to human clinical trials. One of the most regarded effects of statins, in addition to the primary function of lowering cholesterol for which they are clinically prescribed, is the impact on several small guanosine triphosphatases leading to downstream signals that may upregulate NO•
levels and inhibit arginase. However, a better understanding of all the molecular determinants involved in the statin-induced arginase/NOS signaling pathways that lead to potentially protective effects, such as a reduction of cell proliferation, cytotoxicity, or inflammation, is still needed. Therefore, the use of high resolution and sensitive molecular imaging techniques relying on radiolabeled molecules may have the potential to unveil some of the statin-related mechanisms of action by supporting the development of in vitro quantitative techniques to evaluate cellular and subcellular localization and by mapping the biodistribution profile in complex living organisms.
Although the most commonly used statins in the clinic have comparable LDL-lowering efficacy, highly lipophilic statins, such as atorvastatin, seem to have greater pleiotropic benefits [26, 48]. Additionally, atorvastatin has also been regarded as an effective inhibitor of the permeability glycoprotein [54]. This glycoprotein is highly expressed in many tumor cells, conferring resistance to chemotherapy [55]. Thus, the development of 18F-labeled atorvastatin may add
some relevant value, compared to the recently synthesized [18F]pitavastatin,
[11C]rosuvastatin, or other radiolabeled derivatives of statins not corresponding to
the drug actually used in the clinic [56], for the investigation of the potential capacity of statins to suppress arginase activity and/or increase the NO• levels.
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