Roles of Adrenoceptors in Atherosclerosis: Comparison
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Please note this is a comparison between Version 2 by Jessie Wu and Version 1 by Yutang Wang.
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.
 
  • alpha blocker
  • beta blocker
  • blood vessel
  • sympathetic activity
  • atherosclerosis
  • renal denervation

1. Role of α1 Adrenoceptors in Atherosclerosis

α1 blockers have been frequently shown to inhibit atherosclerosis in research animals [68,69,70][1][2][3] and humans [71][4], although certain studies fail to demonstrate a beneficial effect of α1 blockers [72][5]. The anti-atherosclerotic effects of α1 blockers may be mediated by their blood pressure-lowering effect and their favorable effect on lipid profile [68,71,72,73][1][4][5][6]. It has been shown that α1 blockers decrease plasma total cholesterol, very low-density lipoprotein (VLDL), and triglycerides [68,71,72[1][4][5][6],73], and increase high-density lipoprotein (HDL) cholesterol [71][4]. Despite these beneficial effects, α1 blockers may increase the risk of heart failure in the long term [74][7]. The mechanism underlying this side effect is unknown. As α1 adrenoceptors are also expressed in cardiomyocytes [47][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 [51][9]. In addition, α2 activation can lead to a decrease in cytoplasmic Ca2+, which then leads to a decrease in neurotransmitter release [75][10]. Both central and peripheral activation of α2 adrenoceptors can reduce sympathetic activity [51][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 [76][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 [77,78,79,80,81,82,83][12][13][14][15][16][17][18] and clinical studies [84,85][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) [77][12], the second generation of β blockers (selective β1 blockers) [78,79[13][14][19][20],84,85], and the third generation of β blockers (β blockers with additional properties) [80,81,82,83][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 [84[19][20],85], even in the presence of lipid-lowering therapy [85][20]. In these two trials, metoprolol was used at a low dose of 25–100 mg daily in a controlled-release/extended-release formulation [84,85][19][20].
Table 1.
Effect of β blockers (β1/β2 blockers) on atherosclerosis in recent studies.
β Blockers Patients/Animals Effect on

Atherosclerosis		 Mechanism Reference
First Generation: Non-Selective β1 and β2 Blockers
Propranolol BPH/ApoE−/−mice ↓ ↓ HSPC proliferation in the BM

↓ GMPs in the BM

↓ Blood monocytes and neutrophils

↓ Macrophages in the lesion		 [77][12]
Second Generation: β1-Selective Blockers
Metoprolol ApoE−/−mice ↓ N/R [78][13]
ApoE−/−mice ↓ ↓ Circulating TNFα, CXCL1

↓ Macrophages in the lesion		 [79][14]
Subjects without symptoms ↓ N/R [84][19]
Patients with hypercholesterolemia ↓ N/R [85][20]
Third Generation: Non-Selective β Blockers with Additional Properties
Carvedilol

With α1- blocking and antioxidant properties		 Ldlr−/−mice ↓ ↑ ABCA1 in exosomes

↑ Cholesterol efflux

↓ Macrophages in the lesion		 [80][15]
ApoE−/−mice ↓ ↓ Superoxide production

↓ Macrophage and T cell infiltration		 [81][16]
Rabbits ↔ ↓ LDL oxidation

↑ eNOS expression

↑ Endothelium-dependent relaxation		 [82][17]
Nipradilol

With NO-releasing properties		 Rabbits ↓ ↑ eNOS

↑ Endothelium-dependent relaxation

↓ Monocyte adhesion to EC

↓ Monocyte/macrophage infiltration		 [83][18]
Third Generation: β1-Selective Blockers with Additional Properties
Nebivolol

With NO-releasing property		 Rabbits ↓ ↓ LDL oxidation

↓ Inflammatory markers

↑ eNOS expression

↑ Endothelium-dependent relaxation		 [82][17]
↓, decrease; ↑, increase; ↔, no effect; ABCA1, ATP binding cassette subfamily A member 1; ApoE−/−, apolipoprotein E-deficient; BM, bone marrow; BPH, Schlager hypertensive (blood pressure high) mice; CXCL1, CXC motif chemokine ligand 1; EC, endothelial cells; eNOS, endothelial nitric oxide synthase; GMPs, granulocyte-macrophage progenitors; HSPC, hematopoietic stem and progenitor cells; LDL, low-density lipoprotein; Ldlr−/−, LDL receptor-deficient; NO, nitric oxide; NR, not reported; and TNFα, tumornecrosis factor α.
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 [79][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 [77][12]. The third generation of β blockers has other anti-atherosclerotic mechanisms, including promoting cholesterol efflux [80][15], inhibiting oxidative stress [81][16], preventing LDL oxidation [82][17], improving endothelial function [82[17][18],83], and decreasing monocyte adhesion to endothelium [83][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 [53][21]. However, recent studies have reported that β blockers do not affect plasma levels of total cholesterol, triglycerides, or HDL cholesterol [79,81,83,86][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 [87][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 [88][24] and in 14,671 patients with type 2 diabetes and established atherosclerotic cardiovascular disease [89][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 [90][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 [91][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 [92,93,94][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 [92,93,94,95][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		 [92][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		 [93][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		 [94][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		 [95][31]
↓, decrease; ↑, increase; BAT, brown adipose tissue; E3L.CETP mice, APOE*3-Leiden crossing human cholesteryl ester transfer protein mice; HDL, high-density lipoprotein; NR, not reported; TC, total cholesterol; TG, triglyceride; TRL, triglyceride-rich lipoprotein, i.e., very-low-density lipoproteins and chylomicrons; VLDL, very-low-density lipoprotein; and WAT, white adipose tissue.
It is worth noting that β3 agonism does not affect atherosclerosis severity [94][30], lesion composition (smooth muscle cells, collagen, and macrophages), nor the stability of the lesion as assessed by the ratio of stable markers (collagen area or combined collagen and smooth muscle cell area) versus the unstable markers (macrophage area) [92,93][28][29].

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 [54][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 [54,96,97][32][33][34]. It also increases HDL cholesterol, apolipoprotein A1 (ApoA1), and ApoE [96][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 [54,96,97,98][32][33][34][35]. In addition, mirabegron caused QT prolongation in women but not men at the supratherapeutic dose of 200 mg per day [98][35]. These cardiovascular side effects were not significant at the therapeutic 50 mg dose [54,98][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 [96][33]. Therefore, a low dose of mirabegron should be used in future clinical trials investigating the potential anti-atherosclerotic effect of β3 agonism.

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