5-HYDROXYTRYPTAMINE IN THE CARDIOVASCULAR SYSTEM: FOCUS ON THE SEROTONIN TRANSPORTER (SERT)

Authors


Stephanie W Watts, Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824-1317, USA. Email: wattss@msu.edu

SUMMARY

  • 1The function of the serotonin transporter (SERT) is to take up and release serotonin (5-hydroxytyptamine (5-HT)) from cells and this function of SERT in the central nervous system (CNS) is well-documented; SERT is the target of selective serotonin reuptake inhibitors used in the treatment of CNS disorders, such as depression.
  • 2The aim of the present review is to discuss our current knowledge of 5-HT and SERT in the cardiovascular (CV) system, as well as their function in physiological and pathophysiological states.
  • 3The SERT protein has been located in multiple CV tissues, including the heart, blood vessels, brain, platelets, adrenal gland and kidney. Modification of SERT function occurs at both transcriptional and translational levels. The functions of SERT in these tissues is largely unexplored, but includes modulation of cardiac and smooth muscle contractility, platelet aggregation, cellular mitogenesis, modulating neuronal activity and urinary excretion.
  • 4Recent studies have uncovered potential relationships between the expression of SERT gene promoter variants (long (l) or short (s)) with CV diseases. Specifically, the risk of myocardial infarction and pulmonary hypertension is increased with expression of the ll promoter, a variant associated with increased expression and function of SERT. The relationship between promoter variants and other CV diseases has not been investigated.
  • 5Newly available experimental tools, such as pharmacological compounds and genetically altered mice, should prove useful in the investigation of the function of SERT in the CV system.
  • 6In summary, the function of SERT in the CV system is just beginning to be revealed.

INTRODUCTION

Serotonin (5-hydroxytryptamine (5-HT)), as a neurotransmitter in the brain and gastrointestinal tract, is involved in a variety of functions, such as mood control, urine storage and voiding, the regulation of sleep and body temperature, food intake and intestinal motility. 5-Hydroxytryptamine was first found as a powerful vasoconstrictor over a century ago1 and has been recognized as an arterial smooth muscle cell mitogen in the past 20 years.2 In the past decade, a strong argument for the role of 5-HT and the serotonin transporter (SERT) in pulmonary hypertension has been built.3–11 However, the role of circulating 5-HT in the regulation of non-pulmonary, peripheral cardiovascular (CV) function and its contributions to disease are not clear yet. The present review focuses on the effects of 5-HT and its regulator, SERT, on the CV system and initiates a discussion concerning the potential involvement of 5-HT and SERT in CV disease. Because 5-HT is not a hormone commonly associated with the CV system, we will first discuss general aspects of this hormone.

SYNTHESIS AND METABOLISM OF 5-HT

The essential amino acid tryptophan is the precursor for 5-HT. Over 95% of 5-HT in the body is synthesised in the enterochromaffin cells of the intestine, with the remainder synthesised in the raphe nuclei of the brain, neuroendothelial cells that line the lung and a few other discrete sites.12 Some of these sites are in the CV system and will be discussed later. Serotonin synthesis depends on the specific action and rate-limiting step of the enzyme tryptophan hydroxylase, which transfers a hydroxyl group to the benzyl ring of tryptophan. Subsequent decarboxylation by amino acid decarboxylases results in the formation of 5-HT. Bader et al., in knocking out tryptophan hydroxylase (TPH), discovered that two forms of TPH, a peripheral form (TPH1) and a central form (TPH2), are expressed.13,14 This allows for distinct sources of peripheral and central 5-HT. In the periphery, platelets possess a high-efficacy SERT, enabling them to take up 5-HT from the gut and lung. The platelets store 5-HT and release it in a thrombotic event.15 Sites of 5-HT synthesis in the non-pulmonary peripheral vasculature have not yet been identified, so our current understanding is that the systemic vasculature is exposed to 5-HT through the release of 5-HT by the platelet via SERT or to freely circulating 5-HT. Thus, SERT function in the platelet is important because platelets are carriers and storage sites of 5-HT in the periphery.

Metabolism of 5-HT occurs through the actions of monoamine oxidase A (MAOA) to form the metabolite 5-hydroxyindole acetic acid (5-HIAA; Fig. 1). Because MAOA is an intracellular enzyme, 5-HT must be taken up inside a cell prior to being acted upon and both SERT and noradrenaline transporter (NET) facilitate this uptake.16 Tissues or cells that contribute significantly to 5-HT metabolism include the lung, intestine and endothelial cells of the arterial system, but any cell that can take up 5-HT and possesses MAOA has the potential to metabolise 5-HT.

Figure 1.

Depiction of serotonergic synapse and handling of 5-hydroxytryptamine (5-HT) from synthesis, storage, release, uptake and metabolism. 5-HIAA, 5-hydroxyindole acetic acid.

PHARMACOLOGY OF 5-HT

The effects of 5-HT are mediated by interaction with 5-HT receptors, integral proteins of the plasma membrane. At present, seven major families of 5-HT receptors exist (5-HT1−5-HT7) and subtypes exist therein. The reader is directed to recent reviews for more detailed information on 5-HT receptor function.17,18

PHYSIOLOGY OF 5-HT IN THE CV SYSTEM

The aim of the present review is not to provide a thorough evaluation of 5-HT in the CV system; recent reviews detailing the effects of 5-HT in the CV system have been published elsewhere.18,19 Familiarity with the diverse CV functions exerted by 5-HT should precede discussion of the potential that SERT and drugs that alter SERT function may have in the CV system. When discussing the physiological effects of 5-HT, we will discriminate between the effects of exogenous and endogenous 5-HT if and where they are recognized.

Table 1. List of abbreviations:
CVCardiovascularNANoradrenaline
DATDopamine transporterNETNoradrenaline transporter
DOCADeoxycorticosterone acetateSERT Serotonin transporter
5-HIAA 5-Hydroxyindole acetic acidSSRISelective serotonin reuptake inhibitors
5-HT5-Hydroxytryptamine, serotoninTMTransmembrane
MAOAMonoamine oxidase ATPHTryptophan hydroxylase
MIMyocardial infarction  

Platelets

These non-nucleated cells possess SERT and the ability to store, but not synthesise, 5-HT. When platelets aggregate, 5-HT is a primary factor that promotes continued aggregation and the blood vessels in which platelets aggregate are exposed to high concentrations (micromolar) of 5-HT.15

Brain

5-Hydroxytryptamine is a neurotransmitter in the brain and is synthesised within the brain12 with a high concentration localized to the raphe nuclei of the brainstem. Central administration of exogenous 5-HT has been documented to increase and decrease blood pressure and heart rate, depending on the specific site of administration.19–21

Heart

Tryptophan hydroxylase mRNA and protein have been detected in hamster heart22 and 5-HT synthesis has been measured both in an HL-1 cardiomyocyte cell line that represents adult cardiomyocytes and in neonatal rat ventricular cardiac myocytes.23,24 Thus, the cardiomyocyte provides a local source of 5-HT in the heart. 5-Hydroxytryptamine reduces heart rate and can act to inhibit noradrenaline (NA) release centrally.25 In terms of basic function, 5-HT interacts with 5-HT receptors on cardiomyocytes as a positive chronotrope, positive inotrope and mediator of mitogenesis of the cardiac myocyte.26–28

Kidney

Similar to the heart, the kidney has the ability to synthesise 5-HT.29 In the kidney, 5-HT functions as a mesangial cell mitogen, increases renal perfusion pressure when given exogenously30 and promotes sodium retention/phosphate loss.31

Adrenal

5-Hydroxytryptamine and its major metabolite 5-hydroxyindole acetic acid (5-HIAA) have been found in the adrenal gland in multiple species and 5-HT can also be synthesised in chromaffin cells.32–42 In the adrenal, exogenous 5-HT increases NA and adrenaline release and, thus, can affect the CV system by potentially increasing total peripheral resistance.43

Blood vessels

Depending on the species, type of blood vessel and status of the endothelial cell layer, exogenous 5-HT can be a vasoconstrictor or vasodilator. In addition, subcontractile concentrations of 5-HT potentiate arterial contraction to other constrictors, such as angiotensin II, NA and endothelin-1.44,45 This phenomenon likely occurs in vivo. The concentration of free circulating 5-HT in plasma is low and the concentrations of 5-HT at which potentiation of the contraction elicited by other vasoconstrictors is observed (10 nmol/L) are consistent with the concentrations of 5-HT that have been measured in plasma.46 5-Hydroxytryptamine is also a smooth muscle cell and endothelial cell mitogen and, as in the event of contraction, 5-HT can potentiate the mitogenic effect of other hormones.1,47

Collectively, the above work demonstrates the profound and varied effects of 5-HT in the CV system. One can envision that each of these functions has a mechanism to terminate the effects of 5-HT. Uptake and metabolism of 5-HT makes logical sense as a means to stop the actions of 5-HT. Thus, it is reasonable that the mechanisms necessary for uptake of 5-HT (SERT) are present and functional in each system. With this assumption comes the possibility that manipulation of SERT, pharmacologically or genetically, could impact the CV system. Prior to discussing this particular role of SERT, we will discuss several aspects of SERT function and regulation.

THE SEROTONIN TRANSPORTER

Molecular biochemistry

Hoffman and Blakely cloned SERT in 1991 in the rat,48,49 whereas human SERT was cloned in 1993 in placental trophoblastic cells.50 This was followed by cloning of the mouse transporter in 1996.51 Mouse SERT protein has 88% homology with human SERT (compared with rat SERT having 71% homology for human SERT). The SERT proteins are positioned in the plasma membrane. Hydropathy plots of the SERT protein, typically 630 amino acids, have suggested that the protein spans the bilayer 12 times (12 transmembrane (TM) domains) and that both amino and carboxy termini are intracellular (Fig. 1). The SERT protein possesses a large extracellular loop between TM3 and TM4. This loop has sites of glycosylation, important for the trafficking and stability of SERT.52 In three sites of the protein, the amino terminus, the carboxy terminus and the intracellular loop between TM8 and TM9, consensus sites for phosphorylation by protein kinase (PK) C and PKA exist.53 The TM1–TM3 domains are important for interactions with substrates such as 5-HT and TM11 and TM12 are crucial for inhibitor interaction and dependence on cations. Translated SERT protein is of a mass anywhere from 60 to 80 kDa, depending on levels of glycosylation and phosphorylation. In 2000, it was reported that SERT proteins homo-oligomerize,54 but the impact of oligomerization on function is unclear.55 Since this time, SERT has been reported to hetero-oligomerize with myosin IIA,56 noradrenaline transporter (NET)57 and the GABA transporter 1.58

Function and physiology

Serotonin transporter, a sodium-dependent transporter, diminishes the function of 5-HT at its extracellular cognate receptors by removing 5-HT from outside the cell and bringing it back into a cell for metabolism via MAOA or vesicular repackaging. Its basic function is similarly performed by other monoamine transporters, including the dopamine transporter (DAT) and NET and, thus, many of the basic concepts discussed herein apply to these transporters as a family. The present model of SERT functioning (Fig. 2) begins with extracellular sodium binding to the carrier protein. 5-Hydroxytryptamine, in its protonated form, then binds to the transporter and is followed by chloride. This initial complex creates a conformational change in the transporter protein: it revolves from facing extracellularly to an inward-facing position where 5-HT and ions are released in the cytoplasm. Intracellular potassium binds to SERT to promote reorientation of SERT for another cycle to the outside of the cell, at which time K+ is released. These elements (Na+, Cl, 5-HT and K+) are thought to work at a single multifunctional binding site. An interesting characteristic of SERT is that it exhibits 5-HT-gated ion channel activity.59

Figure 2.

Schematic of ionic movement with serotonin transporter function. 5-HT, 5-hydroxytryptamine.

It is reasonably assumed that the function of 5-HT is terminated once brought inside the cell. However, two laboratories have independently demonstrated the necessity of uptake of 5-HT by SERT in mediating pulmonary arterial smooth muscle proliferation to 5-HT.2,3 In addition, a finding in platelets supports the idea that 5-HT, once intracellular, exerts physiological effects. Walther et al.60 demonstrated that 5-HT, actively imported into a platelet by SERT, acts as a substrate for an enzyme class of transglutaminases to covalently modify RhoA or Rab4 with the 5-HT moiety (transamidation or ‘serotonylation’). Serotonylation of RhoA renders it constituitively active. Numerous other protein targets of transglutaminase have been identified.61 Thus, intracellular 5-HT has functional effects. Although the platelet was the initial cell type in which this was demonstrated, it is currently unknown whether intracellular 5-HT can alter function in other cell types from other CV tissues.

Pharmacology

5-Hydroxytryptamine possesses nanomolar affinity (Ki = 17.4 nmol/L) for the rat and human transporters derived from the brain62 and recognition of 5-HT occurs within the first three transmembrane domains of the transporter. The serotonin transporter is best recognized as the site of action of the selective serotonin reuptake inhibitors (SSRIs), examples of which include fluoxetine, citalopram and paroxetine. Fluramines, such as (+)-fenfluramine of the market-withdrawn anorexigen ‘fen-phen’ (fenfluramine–phentermine), exert their effects through a complex interaction with SERT. In neurons, fluramines not only inhibit SERT, but can act as a SERT substrate and cause the release of intracellular 5-HT. This is one mechanism of pathology of (+)-fenfluramine in causing primary pulmonary hypertension63 and aortic valvular disease64 in individuals that took the drug for medical management of obesity. 3,4-Methylenedioxy-methamphetamine (‘ecstasy’) has a similarly complex mechanism of interaction with SERT.65

Regulation

When SERT proteins are artificially expressed in cells, SERT activity is regulated in response to alterations in calcium, calmodulin, PKC, PKA and PKG activity; SERT bears canonical sites for serine/threonine phosphorylation.66–68 Data also support that 5-HT itself may regulate the activation status of SERT, in the absence of 5-HT receptors. Ramamoorthy et al.67 found that in HEK293 cells transfected with SERT but possessing no detectable 5-HT receptors, 5-HT inhibited SERT phosphorylation and decreased the ability of PKC activation to result in decreased SERT activity.67,68 Preservation of SERT function by 5-HT makes logical sense. Recently, Samuvel et al. demonstrated that the p38 mitogen-activated protein kinase (p38 MAPK) regulates SERT because inhibition of p38 MAPK decreased delivery of SERT to the cell surface.69

The SERT promoter in multiple species contains basic elements such as TATA-like, cAMP response element-binding protein (CREB), nuclear factor-κB, AP-2 and SP1 sites.52,53,68 Interestingly, an allele in the human SERT promoter has been found, resulting in 14 (short or s allele) or 16 (long or l allele) repeat elements, a difference of 44 base pairs, and expression of an mRNA species either 484 (s) or 528 (l) base pairs long.70 Possession of the s allele is associated with a lower expression of SERT (estimated at one-third of those possessing two l alleles), resulting in a reduced capability to take up and release 5-HT. In the human, the ss allele has been associated with, but not proven to cause, an inability to handle stressful life events.71 This finding is relevant, because a genetically inheritable difference in alleles suggests that humans, naturally, may express different amounts of SERT throughout the whole body, including the CV system. Recently, ethnic differences in l and s allele frequencies have been noted. In addition, at least 25 different single nucleotide polymorphisms (SNP) of SERT have been reported for the human. The phenotypes, CV or otherwise, of these SNP are not known.71

SEROTONIN TRANSPORTER IN THE CV SYSTEM

Location

Serotonin transporter has been localized to CV tissues using immunohistochemistry, western blot and polymerase chain reaction methodologies. Messenger RNA and/or protein are found in the platelets, pulmonary arteries,4,8 heart,72 systemic arteries (rat aorta, superior mesenteric and carotid arteries73) and endothelial cells. Other tissues important to blood pressure regulation, such as the nucleus tractus solitarius (NTS74) and the adrenal,75,76 have only recently been demonstrated to contain SERT.

Physiology/function

The physiological importance of SERT function is not well studied in many CV-related organs. The best studied is the pulmonary vasculature.

Pulmonary vasculature

In pulmonary endothelial and bovine smooth muscle cells, uptake of 5-HT via SERT is necessary for 5-HT to function as a mitogen. Moreover, Morecroft et al.77 demonstrated that citalopram and fluoxetine inhibited 5-HT-induced contraction of pulmonary arteries isolated from the normal Sprague-Dawley rat. In contrast, these agents potentiated contraction to 5-HT in pulmonary arteries from Fawn-Hooded rats. The Fawn-Hooded rat is a strain with genetically impaired 5-HT storage and reuptake and, interestingly, is susceptible to both pulmonary and systemic hypertension.78 The reason(s) for the differences in the effects of the inhibitors in arteries from Sprague-Dawley versus Fawn-Hooded rats is not well understood. Citalopram also potentiated contraction to 5-HT in the isolated intralobar pulmonary artery in an endothelium-dependent manner in normoxic rats and in an endothelium-independent manner in hypoxic rats.79 The fluramines also cause pulmonary vasoconstriction.80–83 Collectively, these studies suggest that, in the pulmonary vasculature, SERT plays an important role in normal mitogenic and contraction function. The functions supported by SERT in other components of the CV system are not as clear.

Other CV organs

In the mouse adrenal medulla, SERT is required for stress-evoked increases of catecholamine synthesis and angiotensin AT2 receptor expression in the adrenal gland.76 The ability of promoter variants of SERT to influence the function of the CV system is illustrated by studies in platelets. Platelets from humans that possess the l variant of the SERT promoter have a higher Vmax than platelets from humans with no l variants.84

The physiological function of SERT in other CV organs, such as the heart, NTS, peripheral vasculature and kidney, has not been thoroughly investigated. One possible way to determine the role of SERT in CV function is to examine the effect of removal or inhibition of SERT. A mouse that lacks a functional SERT was created by the group of Dennis Murphy.85 Few studies on the physiological CV parameters in these animals have been performed. One can argue that SERT is not critical to the CV system because removal of SERT was not lethal.85 Mice overexpressing SERT have recently been created.8 Systemic arterial pressure was measured in these animals under anaesthesia and it was found that wild-type animals had a pressure of 76.0 ± 3.4 mmHg, whereas the SERT-overexpressing mice had a pressure of 82.9 ± 3.8 mmHg. Similarly, heart rates were not different between wild-type and SERT transgenic mice. These measures may not reflect true blood pressure and heart rate owing to the effects of the anaesthetic. Effects in the adrenal, kidney, brain and heart, as they pertain to the CV system, were not noted and, thus, questions as to the function of SERT in these organs remain unanswered.

As opposed to studies in genetically altered mice, a greater amount of work has been performed investigating the effects of pharmacological inhibition of SERT on CV function.

Platelet function

Inhibitors of SERT decrease platelet 5-HT content, inhibit thrombosis and exacerbate bleeding86 because of prevention of 5-HT reuptake. However, an alternative argument has been proposed. Immediately upon use of SSRIs, platelet 5-HT would not be depleted, but extracellular 5-HT would be higher because of preventing 5-HT reuptake, promoting a thrombosis.87,88 Thus, SERT inhibition may cause dual effects in thrombosis.

Vessel contractility

As noted above, SERT inhibitors have a wide and varied effect on arterial contractility.

Cardiac arrythmias

Compared with the tricyclic group of antidepressants, SERT inhibitors have a decreased ability to induce cardiac arrthymias.89–93 However, citalopram has been reported to increase the QT interval in humans94 and Pacher et al. have published extensive work demonstrating the arrhythmogenic activities of SERT inhibitors, specifically fluoxetine and citalopram, in the hearts of dogs, rabbits, rats and guinea-pigs.95–97

Pathophysiology

In the CV system, SERT has been most strongly implicated in the disease of anorexigen-induced or hypoxia-induced pulmonary hypertension.6 Mice lacking the transporter are relatively resistant to hypoxia-induced pulmonary hypertension and those overexpressing SERT demonstrate a pathology that resembles pulmonary hypoxia, namely pulmonary arterial smooth muscle cell hypertrophy, and cardiac hypertrophy.7,8 In addition, the SERT inhibitors citalopram and fluoxetine protect against hypoxic pulmonary hypertension.9 In humans, pulmonary hypertension was more severe in those possessing the ll genotype compared with those with the ss genotype. The ll genotype is associated with higher SERT expression and activity compared with the ss and ls genotypes.3 Thus, 5-HT and SERT contribute to increased pulmonary blood pressure by dual mechanisms, promoting vasoconstriction and pulmonary artery remodelling. We will next address other CV diseases for which knowledge of the involvement of SERT is just beginning to be accumulated.

SEROTONIN TRANSPORTER IN SYSTEMIC CARDIOVASCULAR DISEASE

Serotonin transporter and hypertension

Role of platelets

Serotonin transporter is unquestionably critical to platelet function. In hypertension, platelet function and SERT activity are changed. The role of platelets in hypertension, as it pertains to 5-HT/SERT, is somewhat unclear because opposite observations of how platelet function changes in hypertension have been made. Although some studies present platelets as hyperaggregatable in hypertension, others, such as in the stroke-prone spontaneously hypertensive rat, show that aggregation of platelets from the hypertensive rat is decreased compared with normotensive controls.98 The rat made hypertensive by administration of the mineralocorticoid deoxycorticosterone acetate (DOCA) is another model in which platelet aggregation is decreased compared with normotensive controls.99 The outcome of a majority of studies is that the content of 5-HT in platelets is decreased.98–100 In theory, these platelets, termed ‘exhausted’ (depleted due to overstimulation), have already been activated early in vivo owing to hypertension.99 In the human, platelets from hypertensive subjects have a lower 5-HT content100 and take up less 5-HT than do platelets from normotensive patients.101

Role of arteries

Our laboratory demonstrated an upregulation of SERT protein density in arteries from DOCA-salt hypertensive rats compared with those from sham normotensive rats.73 This was accompanied by an increased ability of the SERT inhibitor fluvoxamine to leftward-shift contraction to 5-HT in an artery isolated from a DOCA-salt hypertensive rat. This suggests that, functionally, SERT activity in the artery is enhanced in hypertension. It is presently unclear whether SERT function is elevated before or after blood pressure increases and, in turn, how SERT contributes to this disease.

Human condition

Many of the studies cited above were conducted over a decade ago, prior to the discovery of the promoter variants of the SERT gene and useful biochemical tools for detecting SERT. Thus, investigation of SERT expression in human essential hypertension is well worth revisiting. We speculate that the situation of the hypertensive patient is like that of patients possessing an ll allele or increased functional expression of SERT. However, no studies have provided evidence to support the idea that carrying an ll allele places an individual at greater risk of developing hypertension. Moreover, the question remains as to the impact that a change in arterial SERT expression/function may have on hypertension and the association of the platelet with the artery.

Thus, SERT has been implicated in modifying the function of peripheral arteries. The SERT inhibitors are one of the most commonly prescribed drug classes worldwide. Although fluoxetine has been proven to be largely safe, there are reports of fluoxetine-induced acute pressor responses in the rat,102 a sustained hypertension during short-term (12 week) fluoxetine treatment in humans,103 frank hypertension in the rat104 and the use of fluoxetine to treat severe refractory orthostatic hypotension.105 One can interpret these findings to suggest that fluoxetine, in blocking arterial reuptake of 5-HT, may promote arterial contractility. More recently, human serotonin toxicity, including development of hypertension, has been described when the SERT inhibitor citalopram or the SERT/NET inhibitor venlafaxine was used in combination with the oxazolidinone antibiotic linezolid.106 Thus, a local arterial SERT may have an impact on blood pressure.

A search of the US Food and Drug Administration (FDA)-posted drug reports (http://www.fda.gov), using SSRI and hypertension as search terms, revealed that in premarketing clinical studies (thousands of patients), hypertension was listed as a frequent (freq; minimum of 1/100) or infrequent (infreq; minimum of 1/1000) side-effect for the following drugs: fluvoxamine (freq), paroxetine (freq), fluoxetine (freq), escitalopram (freq) and citalopram (infreq). The SERT inhibitors are absolutely contraindicated in patients taking monoamine oxidase inhibitors because this can produce a ‘serotonin syndrome’. This syndrome is characterized by changes in mental status, myoclonus, diaphoresis, hyper-reflexia and, notably, systemic hypertension.107,108 These side-effects are listed explicitly on product sheets for these approved drugs. Moreover, CV disease is a primary comorbid medical condition that prevents physicians from prescribing SSRIs.109 Thus, collective evidence suggests an intriguing relationship between arterial function and SERT as it pertains to hypertension.

Serotonin transporter, depression and CV disease

Serotonin transporter, depression and CV disease are a complex triad of which the interactions are yet to be fully understood. Depression is independently associated with a higher diastolic blood pressure and is significantly related to CV disease and morbidity.110 A recent study showed that the ss genotype of SERT is linked to major depressive disorder.111 Depression is also a risk factor for hypertension112 and myocardial infarction (MI).113,114 Similarly, clinical studies have demonstrated that hypertensive patients and MI patients are more likely to be depressed.112,114 It is unknown whether patients with CV disease are derived from populations with a particular genotype for expression of SERT, such as the ss genotype in the depressed patient. Further complications include whether hypertension and depression are causal in the genesis of the other malady.

Serotonin transporter and MI

Appreciation for the potential influence of SERT on the CV system is growing with recent findings that possessing the ll genotype, resulting in a higher expression and activity of SERT, sets individuals at a significantly higher risk for MI.115 To our knowledge, MI is the only published disease in which CV risk has been associated with presenting a particular gene type.

A recent study of over 5000 individuals demonstrated a marked protection from MI in individuals who took SERT inhibitors/SSRIs and the extent of SERT inhibition among SSRIs correlates with the degree of reduction in MI risk.116 Thus, a lower SERT activity was associated with reduced risk of MI or coronary arterial vasospasm. Similarly, it was hypothesized that the use of SSRIs could also protect against MI by reducing platelet activation and concomitant vasospasm of coronary arteries.117

CONCLUSIONS AND UNANSWERED QUESTIONS

In the present review, we have presented the following conclusions that pertain to SERT in the CV system.

Basic physiology

  • 1Serotonin transporter mRNA, protein and biochemical function have been measured in a variety of different CV tissues.
  • 2Peripheral arteries take up 5-HT via SERT.
  • 3In platelets, SERT modifies 5-HT-induced aggregation.
  • 4Serotonin transporter plays a role in normal pulmonary arterial contraction, pulmonary arterial smooth muscle and endothelial cell mitogenesis.
  • 5Intracellular 5-HT may have a physiological function.

Pathophysiology

  • 1A strong connection of elevated SERT function in pulmonary arteries and pulmonary hypertension has been made.
  • 2Serotonin transporter function in platelets is altered in hypertension.
  • 3The expression of the ll promoter of the SERT gene has been associated with an increased risk of myocardial infarction.

The present review also enables us to arrive at the following questions.

  • 1What is the physiological function of SERT in organs participating in CV regulation (kidney, brain, heart, adrenal, arteries, veins)? Is SERT involved in the pathology of CV disease in these organs?
  • 2What is the CV phenotype of expressing the ss or ll promoter for SERT? Do certain genotypes predispose an individual to CV disease(s) other than MI?
  • 3What is the relationship of SERT, depression and CV disease?
  • 4How does platelet/SERT function change relative to elevated blood pressures?

An issue that crosses all the above questions is whether SERT is the only protein taking up 5-HT in the peripheral CV system. Monoamine transporters, here defined to include NET, DAT and SERT, have the ability to act promiscuously.118 In the peripheral CV system, this promiscuity is exemplified by the uptake and release of 5-HT by adrenergic nerves.16

Other candidates responsible for non-SERT uptake include the organic cation transporters (OCT). The laboratory of Michael Gershon has demonstrated a gastrointestinal upregulation of OCT-1/3 in SERT-deficient mice and, thus, a member of the OCT family is a reasonable candidate for alternative 5-HT uptake.119 The OCT are promiscuous transporters, with substrates as diverse as 5-HT, DA, NA, adrenaline, histamine, clonidine and cimetidine. Pharmacologically, OCT are difficult to distinguish from one another, but can be distinguished from SERT by inhibition by corticosterone, O-methylisoprenaline and levamisole.120,121 Should these alternative candidates be responsible for 5-HT uptake, these are important findings because it means 5-HT uptake/release in the CV system can occur through multiple means.

CONCLUSIONS

This is an exciting time for serotonin research and we now have opportunities to learn a great deal about SERT. The demonstration of the presence of SERT in places previously unexpected, highlighted presently in the CV system, raises the question as to the function of SERT in regulating the response of the cell/tissue in which it is found. Moreover, the discovery of SERT in these places suggests that 5-HT does, in fact, have physiological functions in these tissues. Clearly, SERT is not just for neurons anymore.

Ancillary