Atherosclerosis is an arterial disease that is characterized by the narrowing of the arterial lumen due to the subendothelial accumulation of lipids. Atherosclerosis is the key underlying mechanism for ischemic heart disease and stroke. Despite the availability of a wide array of effective lipid-lowering medications such as statins, ezetimibe, and PCSK9 (proprotein convertase subtilisin-like kexin type 9) inhibitors, ischemic heart disease and stroke remain the leading two causes of mortality globally, highlighting the need to identify new therapeutic strategies for atherosclerosis.
1. Role of α1 Adrenoceptors in Atherosclerosis
α1 blockers have been frequently shown to inhibit atherosclerosis in research animals
[1][2][3] and humans
[4], although certain studies fail to demonstrate a beneficial effect of α1 blockers
[5]. The anti-atherosclerotic effects of α1 blockers may be mediated by their blood pressure-lowering effect and their favorable effect on lipid profile
[1][4][5][6]. It has been shown that α1 blockers decrease plasma total cholesterol, very low-density lipoprotein (VLDL), and triglycerides
[1][4][5][6], and increase high-density lipoprotein (HDL) cholesterol
[4]. Despite these beneficial effects, α1 blockers may increase the risk of heart failure in the long term
[7]. The mechanism underlying this side effect is unknown. As α1 adrenoceptors are also expressed in cardiomyocytes
[8], it is possible that α1 blockers modify gene expression in cardiomyocytes via the α1 adrenoceptor-stimulatory Gs protein pathway and consequently weaken the structure or function of the heart over a long period of time.
2. Role of α2 Adrenoceptors in Atherosclerosis
α2 activation leads to activation of the inhibitory Gi protein which inhibits adenylate cyclase and decreases intracellular cAMP
[9]. In addition, α2 activation can lead to a decrease in cytoplasmic Ca
2+, which then leads to a decrease in neurotransmitter release
[10]. Both central and peripheral activation of α2 adrenoceptors can reduce sympathetic activity
[9].
The involvement of α2 adrenoceptors in atherosclerosis is not clear. A recent study has shown that moxonidine, an agonist for α2 and imidazoline 1 (I1) receptors, inhibits atherosclerosis in apolipoprotein E-deficient (ApoE
−/−) mice
[11], possibly via inhibiting inflammation and promoting oxidized LDL uptake and clearance. This anti-atherosclerotic effect seems to be mediated by α2 adrenoceptors as the effect of moxonidine on oxidized LDL uptake by cultured vascular smooth muscle cells was inhibited by the α2 antagonist RX821002; in addition, activation of I1 by AGN192403 did not replicate the effects of moxonidine on oxidized LDL uptake. The role of α2 adrenoceptors in atherosclerosis needs to be investigated in the future using specific α2-agonists.
3. Role of β1 Adrenoceptors in Atherosclerosis
Many preclinical
[12][13][14][15][16][17][18] and clinical studies
[19][20] have been conducted in recent years to investigate the effect of β blockers on atherosclerosis (
Table 1). It has been shown that the first generation of β blockers (non-selective β1/β2 blockers)
[12], the second generation of β blockers (selective β1 blockers)
[13][14][19][20], and the third generation of β blockers (β blockers with additional properties)
[15][16][17][18] attenuate atherosclerosis progression. In particular, two randomized controlled trials showed that the selective β1 blocker metoprolol reduced the rate of atherosclerosis progression
[19][20], even in the presence of lipid-lowering therapy
[20]. In these two trials, metoprolol was used at a low dose of 25–100 mg daily in a controlled-release/extended-release formulation
[19][20].
Table 1. Effect of β blockers (β1/β2 blockers) on atherosclerosis in recent studies.
β blockers inhibit atherosclerosis via multiple mechanisms including inhibiting inflammation (
Table 1). For example, the β1-selective blocker metoprolol decreases the circulating level of proinflammatory cytokines and chemokines and decreases the macrophage content in the lesion
[14]. Similarly, the non-selective inhibition of β1 and β2 adrenoceptors by propranolol decreases the production of granulocyte-macrophage progenitors (GMPs) in the bone marrow and decreases the circulating numbers of monocytes and neutrophils
[12]. The third generation of β blockers has other anti-atherosclerotic mechanisms, including promoting cholesterol efflux
[15], inhibiting oxidative stress
[16], preventing LDL oxidation
[17], improving endothelial function
[17][18], and decreasing monocyte adhesion to endothelium
[18].
It is worth noting that some studies have shown that β blockers (non-selective β1/β2 blockers or selective β1 blockers) have adverse effects on plasma lipoprotein levels such as increasing VLDL and decreasing HDL cholesterol, and, therefore, β blockers are currently discouraged for use to prevent atherosclerosis
[21]. However, recent studies have reported that β blockers do not affect plasma levels of total cholesterol, triglycerides, or HDL cholesterol
[14][16][18][22].
In addition, the relationship between the baseline use of β blockers and clinal outcomes in epidemiological studies is inconsistent. For example, it has been reported that baseline β1 blocker use was associated with lower 30-day and 10-year mortality in 3371 patients undergoing major vascular surgery
[23]. However, it has also been reported that baseline β blocker use was associated with an increased cardiovascular event risk in 11,785 patients undergoing infrainguinal revascularization for critical limb ischemia
[24] and in 14,671 patients with type 2 diabetes and established atherosclerotic cardiovascular disease
[25]. Moreover, Cimaglia et al. found that baseline β blocker use was not associated with an increased cardiovascular event risk in 618 diabetic patients with the most advanced stage of peripheral artery disease
[26]. Therefore, more randomized controlled trials are needed to establish the merit of the use of β blockers for atherosclerosis inhibition and cardiovascular risk reduction.
4. Role of β2 Adrenoceptors in Atherosclerosis
Whether β2 adrenoceptors play a role in atherosclerosis is unknown and this is worthy of investigation in the future. It has been shown that the selective blockade of β2 adrenoceptors could reduce inflammation and oxidative stress
[27], suggesting that β2 adrenoceptors may be involved in atherosclerosis.
5. Role of β3 Adrenoceptors in Atherosclerosis
5.1. Preclinical Studies
β3 agonists inhibit atherosclerosis in mice fed with a Western-type diet in preclinical studies
[28][29][30] (
Table 2). They inhibit atherosclerosis via multiple mechanisms, e.g., (1) activating brown adipose tissue and thus increasing fat oxidation and decreasing body fat mass, (2) increasing the clearance of plasm triglyceride-rich lipoprotein (TRL), i.e., VLDL and chylomicrons, via increasing the liver uptake of VLDL core remnants and thus decreasing plasma non-HDL cholesterol, (3) increasing HDL cholesterol via promoting the transfer of TRL particles to HDL particles, (4) increasing lipoprotein lipase lipolysis activity and thus decreasing plasma triglycerides, and (5) decreasing total cholesterol
[28][29][30][31]. The resultant favorable lipid profile may explain the anti-atherosclerotic effect of β3 agonism.
Table 2. Effect of β3 agonism on atherosclerosis in preclinical studies.
β3 Agonist |
Animals |
Effect on Atherosclerosis |
Mechanisms |
Reference |
CL316,243 |
E3L.CETP mice |
↓ |
↑ Energy expenditure ↑ Fat oxidation by activated BAT ↓ Total body fat mass ↓ Lipid droplet content in BAT ↓ Plasma TG, TC, and non-HDL cholesterol ↑ Plasma TRL clearance ↑ Hepatic cholesterol content ↑ HDL cholesterol |
[28] |
CL316,243 |
E3L.CETP mice |
↓ |
↓ TC and TG ↑ VLDL clearance ↑ Liver uptake of VLDL core remnants ↑ Lipoprotein lipase lipolysis activity ↑ Transfer of VLDL to HDL cholesterol ↑ Plasma HDL cholesterol |
[29] |
CL316,243 |
E3L.CETP mice |
↓ |
↓ Total fat mass ↓ Plasma TG and non-HDL cholesterol ↑ Plasma clearance and hepatic uptake of cholesterol-enriched TRL remnants. ↑ HDL cholesterol |
[30] |
CL316,243 |
E3L.CETP mice |
NR |
↓ Body fat masss and gonadal WAT ↓ Plasma TG, TC, and non-HDL cholesterol ↑ Clearance of TRL-like particles ↑ Hepatic uptake of TRL-like remnants ↑ Tranfer of TRL particles to HDL particles ↑ Plasma HDL cholesterol |
[31] |
5.2. Clinical Studies
β3 adrenoceptors are expressed in a species-specific manner. For example, in mice, they are most highly expressed in white and brown adipose tissues, whereas in humans they are most highly expressed in the urinary bladder
[32]. A β3 agonist mirabegron (Myrbetriq, extended-release tablet, Astellas Pharma) has been approved for the treatment of overactive bladder, with an approved maximum dose of 50 mg per day.
β3 agonism by mirabegron increases brown adipose tissue volume, brown adipose tissue metabolic activity, lipolysis, fat oxidation, and resting energy expenditure in humans
[32][33][34]. It also increases HDL cholesterol, apolipoprotein A1 (ApoA1), and ApoE
[33]. These results suggest that β3 agonism may inhibit atherosclerosis in humans.
It is worth noting that high doses of mirabegron have unfavorable cardiovascular effects. Mirabegron increased the heart rate, blood pressure, and rate-pressure product (an indicator of myocardial oxygen consumption) in clinical trials at doses higher than the approved maximum therapeutic dose of 50 mg per day
[32][33][34][35]. In addition, mirabegron caused QT prolongation in women but not men at the supratherapeutic dose of 200 mg per day
[35]. These cardiovascular side effects were not significant at the therapeutic 50 mg dose
[32][35]. The reason for the high-dose mirabegron-induced cardiovascular stimulation is unknown. It is possible that the high dose of mirabegron is taken up by sympathetic nerve terminals which causes the release of norepinephrine and activation of β1 adrenoceptors in cardiomyocytes
[33]. Therefore, a low dose of mirabegron should be used in future clinical trials investigating the potential anti-atherosclerotic effect of β3 agonism.