Human β-Defensin 2 Is a Novel Opener of Ca2+-Activated Potassium Channels and Induces Vasodilation and Hypotension in MonkeysNovelty and Significance
Human β-defensin 2 (HBD2) is a cysteine-rich cationic antimicrobial peptide known for its important role in innate immune system. Intensive studies have demonstrated its antimicrobial and chemotactic activities in vitro. In this study, ELISA analysis showed that HBD2 was significantly downregulated in sera of patients with hypertension. It relaxed vessel smooth muscle by acting on the major regulatory pathways, contributing to vessel smooth muscle contraction. Electrophysiology analysis indicated that HBD2 acted as an opener of large-conductance Ca2+-activated potassium (BKCa)-mSlo+hβ1 channels and increased BKCa currents. Mutation analysis revealed that HBD2 activated BKCa-mSlo+hβ1 channels via interacting with Leu41 and Gln43 of β1-loop. In vivo experiments suggested that HBD2 at 4× to 6× of physiological concentration exerted hypotensive effect in monkeys significantly, whereas the selective blocker of BKCa channels, Paxilline, inhibited the effect. HBD2 is the first peptide opener of BKCa-mSlo+hβ1 channels. It may be a novel regulator of blood pressure and provides a new therapeutic target for the treatment of hypertension. The HBD2 blockade of the BKCa channels may represent a new type of cross-talk between immune and cardiovascular systems.
Defensins belong to a major family of antimicrobial peptides, playing a crucial role in the innate immune system because of their antimicrobial activities, and are expressed chiefly in various epithelial tissues.1–3 Based on their cysteine motifs, they can be classified into 2 main classes, α- and β-defensins. β-defensins are composed of 38 to 42 amino acids with the cysteine arrangement of C1-C5, C2-C4, and C3-C6.2 In humans, 4 β-defensins (HBD1-4) have been identified and characterized to date, although >28 β-defensin genes have been found in the human genome.1,4
β-Defensins are cysteine-rich, cationic, and low molecular weight peptides. Structurally, they are characterized by a β-sheet structure linked by 3 disulfide bonds, which are formed by 6 cysteine residues. Sharing a striking degree of conservation with β-defensins, some neurotoxins could act on ion channels effectively, such as the crotamine family from South American rattlesnakes.5,6 It has been found that bolus systemic administration of defensins leads to neurotoxic- and cytotoxic-like effects.5–8
The large-conductance Ca2+-activated potassium (BKCa) channels are expressed broadly on smooth muscle cells (SMCs) and play an important role in the regulation of vascular tone.9,10 BKCa channels are typically composed of 4 pore-forming mSlo α subunits with/without its auxiliary β subunits. The β-family of BKCa channels has 4 distinct mammalian β-subunits (β1-β4) distributed in a variety of native tissues with significant diversity in the functional characteristics. BKCa-type channels have diverse physiological roles; for example, the β1 subunit in SMCs plays a vital role in coupling Ca2+ influx with BKCa currents responsible for hypertension.11–13 The openers of BKCa-type channels, especially of the mSlo+β1 channel, have received a great deal of attention attributable to the fact that they can be used to treat various cardiovascular diseases. Up to now, no peptidyl opener of BKCa-mSlo+β1 channels has been reported, although there are a variety of nonpeptidyl BKCa openers; for example, puerarin, an isoflavonoid derived from radix puerariae, induces vasodilation by potentiating mSlo+β1 channels.14–16
Human Plasma HBD2 Measurements
Human plasma HBD2 measurements were performed as approved by the Ethics Committee of Kunming Institute of Zoology, Chinese Academy of Sciences. Detailed methods can be found in the online-only Data Supplement.
Recombinant Expression of HBD2 and Its Mutations
Host strain Escherichia coli BL21 (DE3) and plasmid pET-32a (+) were used to express recombinant HBD2 (rHBD2) and its mutations, including rHBD2-I, DEF-DelN, DEF-DelN&C, DEF-DelC-I, and DEF-DelC-II. Detailed methods can be found in the online-only Data Supplement.
Western Blot Analysis
Rat aortic vascular SMCs (VSMCs; PriCells, China) were cultured in DMEM/F12 (HyClone) supplemented with 10% fetal bovine serum, and early passaged VSMCs (<4 passages) were used in the experiment. See the online-only Data Supplement for a detailed description.
Cell Culture and Transfection
HEK 293 (human embryonic kidney 293) cells were transfected with the cDNA (mSlo/mSlo-mutation, hβ/hβ-mutation, and SK3 [small-conductance Ca2+-activated potassium channel, subtype SK3]) as described (see the online-only Data Supplement for details).
All experiments in excised patch configurations were performed and recorded using the Axon 200B patch-clamp amplifier and pClamp software (Axon Instruments, Inc, USA). Detailed methods can be found in the online-only Data Supplement.
Measurement of Blood Flow Rate
Laser speckle imaging technique was used to measure the flow rate of blood. The schematic diagram of the experimental setup is shown in Figure 5A. Detailed methods can be found in the online-only Data Supplement.
Effects of rHBD2 on Blood Pressures of Rats and Monkeys
Sprague-Dawley rats (male, specific pathogen free, 160–185 g body weight [BW]) were used as approved by the Ethics Committee of Kunming Institute of Zoology, Chinese Academy of Sciences.
Nine healthy male rhesus monkeys that were 7 to 9 years of age and varied in weight from 7.5 to 8.5 kg were used as experimental subjects. All animal care and experimental procedures were approved by the Animal Care and Use Committee at Kunming Institute of Zoology, Chinese Academy of Sciences. Detailed methods can be found in the online-only Data Supplement.
Six monkeys were used for the test. Detailed methods can be found in the online-only Data Supplement.
The statistical analysis was performed using the statistical software SPSS 16.0 for Windows (SPSS, Chicago, IL). Data are presented as mean±SD, unless indicated. Significance was accepted at the following levels: *P<0.05, **P<0.01, ***P<0.001. Comparisons were determined by 1-way, 2-tailed ANOVA followed by Tukey post hoc tests (for multiple comparisons) or unpaired t test (for 2 groups).
Low Level of HBD2 in Patient Plasma With Hypertension
As illustrated in Figure 1A, HBD2 is significantly downregulated in sera of newly identified patients with hypertension who do not take any medicines. The study population consisted of 161 healthy controls (average age: 47.86; women: 84; men: 77; average systolic pressure: 124.84; average diastolic pressure: 81.16) and 166 newly identified patients (average age 48.52; women: 84; men: 82; average systolic pressure: 159.84; average diastolic pressure: 99.59) with hypertension. The mean plasma HBD2 level of healthy controls (79.87±57.4 pg/mL) was higher than that of patients (53.56±32.63 pg/mL), the difference was statistically significant (P=0.013).
rHBD2 Inhibited 20-kDa Myosin Light Chain and Myosin Phosphatase Target Subunit 1 Phosphorylation and Increased RhoA Phosphorylation
The discovery of low concentration of HBD2 in patient plasma with hypertension made us try to find the possible connection between this defensin and hypertension. The major regulatory mechanism of smooth muscle contraction is phosphorylation /dephosphorylation of the 20-kDa myosin light chain (MLC20). To investigate the effect of rHBD2 (Figures S1 and S2 in the online-only Data Supplement) on MLC20 phosphorylation at Ser19, VSMCs were treated with 10 μmol/L rHBD2 for 0 (control), 2.5, 5, and 10 minutes, respectively. Western blot analysis showed rHBD2 significantly inhibited MLC20 phosphorylation in a time- and dose-dependent manner (Figure 1B, Figure S3). The MLC20 dephosphorylation was accompanied with myosin phosphatase target subunit 1 (MYPT1) dephosphorylation at Thr696 (Figure 1C). As an upstream signaling molecule, RhoA phosphorylation on Ser188 was also detected. Figure 1D illustrates that rHBD2 increased phosphorylations of RhoA Ser188 in a time-dependent manner.
Activation of BKCa-mSlo+hβ1 Channels by rHBD2
We recorded the macroscopic BKCa currents in HEK 293 cells coexpressing mSlo and hβ1 in outside-out patches, in the absence and presence of 100 nmol/L rHBD2 at 1 μmol/L intracellular Ca2+ 100 nmol/L rHBD2 increased the currents of BKCa-mSlo+hβ1 channels significantly (Figure 2A, left), and resulted in a 25-mV leftward-shift of conductance-voltage relationship (G-V) curves (Figure 2A, right). However, it did not significantly alter the G-V curves of both the BKCa-mSlo and BKCa-mSlo+hβ2 channels (Figure 2B), suggesting that rHBD2 is in favor of interacting with hβ1.
The time course of currents after application of 100 nmol/L rHBD2 indicated that the whole process rose up in a rapid way, and fell down in an almost irreversible manner after removing rHBD2. The rising time constant τon was 28.6 s during applying rHBD2, and the time constant τoff of partial recovery (<50%) was 196 s after removing rHBD2 (Figure 2C), which implied the longer recovery time or the higher affinity between rHBD2 and channel. Dose–response experiments using HEK 293 cells coexpressing mSlo and hβ1 subunits were obtained from outside-out patches at +70 mV, in the presence of 0, 0.1, 1, 10, 100 nmol/L rHBD2 at 1 μmol/L Ca2+, respectively (Figure 2D). The dose–response curve of rHBD2 fits to a Hill equation with an EC50 of 1.4 nmol/L and a Hill coefficient of 0.53, suggesting that there is only 1 binding site.
Effect of rHBD2 on the Single-Channel Currents of BKCa-mSlo+hβ1
To further confirm whether rHBD2 truly activated BKCa-mSlo+hβ1 channels, we examined the effect of rHBD2 on single-channel activity of BKCa-mSlo+hβ1 channels. The single-level activities of mSlo+hβ1 channels were recorded in an outside-out patch at +70 mV with and without 100 nmol/L rHBD2, in the presence of 1 μmol/L intracellular Ca2+ (Figure 2E). The control NPO (the multichannel open probability) was 1.03 (left), and the NPO with 100 nmol/L rHBD2 was increased to 1.38 (right). The summary data for the effect of 100 nmol/L rHBD2 on single BKCa channels showed a voltage-dependent potentiation in NPO, that is, 314.3±124.1%, 290.5±118.3%, 208.1±30.4%, 114.3±31.5%, and 33.8±9.7% for −80, −40, −20, +40, and +70 mV (Figure 2F), respectively, suggesting that the potentiating effect of rHBD2 rapidly reduces at the voltages higher than +70 mV because of saturation of open probability. In Figure 2G, the current–voltage curve shows no significant change in single-channel conductance before and after the application of 100 nmol/L rHBD2 (269.1±15.1 [control] and 266.0±22.6 pS [rHBD2]). In Figure S4, a set of rHBD2 mutations exhibited the similar potentiation on BKCa currents, but the DEF-DelC-I gave rise to the least effect, suggesting that its C terminus had less importance than other domains.
Interacting Sites Between rHBD2 and hβ1-Loop
To determine the binding domain of rHBD2 in hβ1-loop, we replaced the N terminus of hβ1-loop with the corresponding segments of hβ2-loop (Figure 3A), because rHBD2 did not potentiate the hβ2 currents (Figure 2B). Three mutants, hβ1-C1(hβ2), hβ1-C2(hβ2), and hβ2-C1(hβ1), showed a small change induced by 100 nmol/L rHBD2 in the V50s of G-V curves, that is, ΔV50=8.8 mV for hβ1-C1(hβ2), as in Figure 3C, ΔV50=5.0 mV for hβ1-C2(hβ2), as in Figure 3D, and ΔV50=10.0 mV for hβ2-C1(hβ1), as in Figure 3E, suggesting that the C1-TM1 (transmembrane domain) segment was possibly the interaction domain, comparing with the 25-mV shift of hβ1 (Figure 3B). Because the residues Glu13/Thr14 were located at the end of the β1 N terminus, we inferred that they should be a pivot for delivering binding information from outside to inside. Indeed, the hβ1(E13Q/T14Q) removed half the potentiation of rHBD2 (Figure 3F). Additionally, the mutations hβ1(K44A) and hβ1(K44A/K52A) did not alter potentiation, suggesting that it may be a nonelectrostatic effect (Figure 3K and 3L). Therefore, we turned our attention to the other remaining residues. Among the mutants hβ1(P40R), hβ1(L41S), hβ1(Y42A), and hβ1(Q43M), as in Figure 3G–3J, we only found that the hβ1(P40R), as in Figure 3G, and the hβ1(Y42A), as in Figure 3I, mutations allowed a larger left-shift ΔV50>20 mV, suggesting that Leu41 and Gln43 of hβ1 should be at the interacting sites of rHBD2 and hβ1-loop. To further investigate whether rHBD2 interacts with mSlo directly, we tried to explore the S3-S4 linker region of mSlo, which was located at the extracellular domain of channel. Three mutants, mSlo(S202A), mSlo(W203A), and mSlo(L204A), were made for this purpose (Figure 3M–3O). However, they did not markedly reduce the potentiation of rHBD2 (Figure 3P).
rHBD2 Enhancing the BKCa Currents in VSMCs
To examine whether rHBD2 has potentiation effect on hyperpolarization, the BKCa currents in VSMCs were recorded in outside-out patches. To identify the BK-type channels of VSMCs, a specific BKCa blocker, 10 μmol/L Paxilline was used for this purpose.17 In Figure 4A, we found that it had a similar activation time constant with the expressed BKCa-mSlo+hβ1 in HEK 293 cells, compared with the typical fast activation time constant of mSlo, indicating that the BK-type channel of VSMCs does contain the β1 subunits. Single-channel recording data in VSMCs showed a similar potentiation of 100 nmol/L rHBD2 on BK-type channel in VSMCs (Figure 4B–4D) just as we had seen previously in HEK 293 cells (Figure 2E–2G). The single-channel NPO at +80 mV increased from 0.083 (control) to 0.169 (100 nmol/L rHBD2; Figure 4B). A summary of the effect of 100 nmol/L rHBD2 on single BKCa channel in VSMCs revealed again the voltage dependence of NPO, that is, 72.7±26.5% for +80 mV, and 49.3±15.3% for +100 mV (Figure 4C). In Figure 4D, the current amplitudes of the BK single channels showed no significant change before and after the application of 100 nmol/L rHBD2 (20.98±1.13 and 21.42±1.36 pA for +80 mV, 25.89±1.25 and 26.25±1.65 pA for +100 mV).
To further examine the specificity of rHBD2 on BK-type channels, 100 nmol/L rHBD2 was used to test whether it could enhance the currents of SK3 channels. In Figure S5, the SK3 currents evoked by a voltage ramp were blocked by the SK3 blocker, 200 nmol/L Scyllatoxin, but not potentiated by 100 nmol/L rHBD2, in the presence of 0.8 μmol/L Ca2+, suggesting that rHBD2 is a specific potentiator of BK channels.
rHBD2 Decelerated the Blood Flow Rate
To explore the physiological role of rHBD2 on mice in vivo, we examined the changes of artery blood flow rates before and after injection of rHBD2. Laser speckle imaging technique was used to measure the flow rate of blood on mesenteric microcirculation (Figure 5A and 5B). At the dose of 90 μg/kg BW, rHBD2 diluted with Ringer’s solution (20 μg/mL) obviously decelerated the flow rate of blood after treatment for 5 minutes, whereas the same dose of Ringer’s solution without rHBD2 had no significant effect (Figure 5C and 5D). The effect can be reversed by injection of Paxilline (40 μg/mL, 150 μg/kg) after rHBD2 treatment. The summary data are shown in Figure 5E. The normalized rates were 1.029±0.031, 0.819±0.081, and 1.009±0.158 for Ringer’s solution, rHBD2, and Paxilline, respectively.
Effects of rHBD2 on Blood Pressures of Rats and Monkeys
Rats were used to test effects of rHBD2 on blood pressures in a dose-dependent manner as illustrated in Figure S6. At the dose of 90 μg/kg BW, rHBD2 obviously lowered systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean blood pressure (MBP). After treatment for 5 minutes, the SBP was decreased from 132.6±15.08 mm Hg to 96.5±6.36 mm Hg, whereas the DBP and MBP were decreased from 101.8±10.76 mm Hg and 110.4±12.44 mm Hg to 79±9.9 mm Hg and 84.5±9.19 mm Hg, respectively; this effect weakened gradually in the following tested period and, finally, the blood pressure returned to near the normal level at 20 minutes. Compared with high-dose group, the blood pressure also decreased at the time point of 5 minutes after middle-dose rHBD2 (60 μg/kg BW) administration, but the trend became weaker. The low-dose group (30 μg/kg BW) induced no obvious changes on SBP, DBP, or MBP.
According to dose-dependent effects of rHBD2 on blood pressures of rats, we selected the dose of 90 μg/kg BW for the monkey experiments. rHBD2 administration significantly lowered the blood pressures of monkey (monkey 4–9), whereas 0.9% salt water had no effect on the blood pressures (monkey 1–3; Figure 6). The time courses of blood pressures (SBP, DBP, and MBP) for individual monkey before and after 90 μg/kg BW rHBD2 treatment are shown in Figure 6. SBP, DBP, and MBP values of 5 monkeys (monkey 4, 5, and 7–9) were all significantly decreased after rHBD2 administration. For example, the mean value of SBP, DBP, and MBP of monkey 4 decreased from 130.4±5.72, 72.3±5.68, and 91.8±3.52 mm Hg (before rHBD2 injection, 0–30 minutes) to 110.11±9.29, 56.44±9.15, and 75.89±8.34 mm Hg, respectively, at 75 to 103 minutes segment; 16 to 20 mm Hg was decreased by 90 μg/kg BW rHBD2. The mean value of SBP, DBP, and MBP of monkey 5 decreased from 151.25±7.35, 93.17±10.97, and 112.67±8.46 mm Hg (before rHBD2 injection, 0–35 minutes) to 128.8±6.39, 75.1±4.68, and 93.6±4.62 mm Hg, respectively, at 76 to 107 minutes segment; 18 to 22 mm Hg was decreased by 90 μg/kg BW rHBD2. For monkey 6, the mean value of SBP, DBP, and MBP decreased from 115.13±6.17, 56.63±5.76, and 75.25±6.54 mm Hg, respectively, before rHBD2 injection (0–35 minutes) to 108.67±3.39, 47.22±1.99, and 69.11±1.76 mm Hg, respectively, at 51 to 71 minutes segment and then recovered to 120.18±6.71, 56.53±5.69, and 77.82±4.82 mm Hg, respectively, after 72 minutes. Only 6 to 9 mm Hg was decreased by 90 μg/kg BW rHBD2 in this monkey. Probably, this different drug response of each monkey was attributable to the animal individual differences.
As illustrated in Figure S7, the selective blocker of BKCa channels, Paxilline (90 μg/kg BW), blocked completely the effects of rHBD2 (90 μg/kg BW) on monkey blood pressure, whereas Paxilline alone had no effects on blood pressure.
Pharmacokinetics Analysis of rHBD2 in Monkeys
As illustrated in Figure S8, there was a basic HBD2 concentration of 100 to 150 pg/mL in monkey serum. After 90 μg/kg BW rHBD2 treatment for 60 to 80 minutes, the highest rHBD2 concentration (550–840 pg/mL) was observed. The rHBD2 concentration was decreased after rHBD2 treatment for 80 to 100 minutes.
HBD2 has important functions in both the innate and adaptive immune responses and is mainly expressed in epithelial cells, monocytes, macrophages, dendritic cells, and keratinocytes.1,18 HBD2 is inducible by bacteria or their products (eg, lipopolysaccharide), and various proinflammatory cytokines (eg, tumor necrosis factor-α and interleukin 1β).19 We found that there was a significant lower level of HBD2 in sera of patients with hypertension (Figure 1A), which gave rise to our interest to investigate possible connection between HBD2 and blood pressure.
The myosin light chain phosphatase dephosphorylates MLC20 and relaxes smooth muscle. Activity of myosin light chain phosphatase was enhanced by dephosphorylation of its regulatory MYPT1.20 Phosphorylation and inhibition of small GTPase RhoA will inhibit Rho kinase which, in turn, dephosphorylates the MYPT1 and then increases the myosin light chain phosphatases activity.20–22 rHBD2 inhibited MLC20 and MYPT1 phosphorylation and increased RhoA phosphorylation (Figure 1B–1D). These results suggest that rHBD2 dephosphorylates MLC20 and MYPT1 by inhibiting RhoA and, thus, relaxes smooth muscle and lowers blood pressure.
The rHBD2 is the first peptide that exclusively potentiates the mSlo+hβ1 channels from the extracellular side of cell membranes (Figures 2–4). It is well known that the BKCa-mSlo+β1 channel as well as the β1 subunit was a vasoregulator in the arterial SMCs, which play a vital role in hypertension.11 However, the regulating mechanism of β1 is not fully clear. Our results suggest 2 possible signaling pathways between rHBD2 and hypertension: (1) HBD2→BK channel activation→membrane hyperpolarization→relaxation; and (2) HBD2→RhoA→myosin light chain→relaxation.
All results mentioned above (low concentration of HBD2 in patient sera with hypertension, induction of dephosphorylation of MLC20, and specifically acting on BKCa-mSlo+hβ1) suggest that HBD2 could act as a vasodilator and lowers blood pressure in vivo. Rhesus monkeys were selected as the study subjects because monkey β-defensin 2 shared high protein sequence similarity with HBD2 (99%). rHBD2 significantly lowered blood pressures in the monkey (Figure 6). In addition, it also lowered blood pressures in rats (Figure S6), but the duration time to lower blood pressures in rats is much shorter than that in monkeys. Considering the maximal identity between HBD2 and rat defensins is only 50%, different ligands and BK channels among these species may contribute different responses induced by rHBD2 administration. As illustrated in Figure 5D and Figure S7, the selective blocker of BKCa channels, Paxilline, blocked completely the effects of rHBD2 on blood pressures of mice and monkeys, which also demonstrated that rHBD2 acts on BKCa channels.
The highest rHBD2 concentration (550–840 pg/mL) was observed in the monkey serum after 90 μg/kg BW rHBD2 was administered for 60 to 80 minutes (Figure S8), while the significant hypotensive effect was also observed (Figure 6). Compared with the basic concentration of HBD2 (100–150 pg/mL) in monkey serum, HBD2 at 4× to 6× of physiological concentration significantly exerted hypotensive effect in monkeys.
In the present work, we demonstrated that rHBD2 could reduce the blood flow rate; however, an obvious relaxation in diameters of blood vessel was not directly observed. In fact, the issue on whether the BK (β1) modulators can affect the diameter of arterioles is in debate for a long time. Liu et al23 reported that the IBTX (iberiotoxin), a specific blocker of BK channels, cannot change the diameters of the Wistar Kyoto pial arterioles. In our in vitro experiments in rats, we found that IBTX depressed the diameters of the rat arterioles so small that we cannot make sure it really works. Similarly, we found the rHBD2 affected the diameters of arterioles so slightly that we could not confirm it in only 1 arteriole. Changes in both the blood stream and the blood pressure can better represent the effects of rHBD2 on the whole arteriole system.
Finally, we report that HBD2 acts as a peptidyl BKCa-mSlo+β1 channel opener and lowers monkey blood pressures. Our findings could be important for better understanding the mechanism of BKCa openers lowering blood pressure and improving cardiovascular symptoms. In addition, HBD2, a known immune molecule, was found specifically to activate BKCa-mSlo+β1 channel, lower blood pressures in rats and monkeys, and likely relax smooth muscle by acting on the major regulatory pathways contributing to contraction of smooth muscle (MLC20 phosphorylation, Figure 1B–1D). These results also provide a new type of cross-talk between immune and cardiovascular systems. HBD2 may be a regulator of blood pressure and provides a new therapeutic target for the treatment of hypertension.
The results of the present study show that HBD2 may have an important role in the regulation of blood pressure. The ability of HBD2 to activate BKCa-mSlo+hβ1 channels and to lower blood pressures of monkey suggests that it seems to have protective effects in the vascular system. Further studies are needed to establish whether HBD2 has the potential to become a valuable therapeutic agent in cardiovascular disease.
We thank Dr Yingliang Wu for kindly providing cDNA of SK3 and Scyllatoxin and Professor Jose M.C. Ribeiro for article revision and comments.
Sources of Funding
This work was supported by the Chinese National Natural Science Foundation (31070701, 31000962, 31025025, 30971179, 31170814, 30972848, 31028006), the Ministry of Science and Technology (2010CB529800, 2009ZX09103-1/091, 2011ZX09102-002-10), and the Ministry of Agriculture (2009ZX08009-159B), and Fundamental Research Funds for the Central Universities (2010ZD028).
The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.111.01076/-/DC1.
- Received January 17, 2013.
- Revision received February 11, 2013.
- Accepted May 10, 2013.
- © 2013 American Heart Association, Inc.
- Hazrati E,
- Galen B,
- Lu W,
- Wang W,
- Ouyang Y,
- Keller MJ,
- Lehrer RI,
- Herold BC
- Ledoux J,
- Werner ME,
- Brayden JE,
- Nelson MT
- Navarro-Antolín J,
- Levitsky KL,
- Calderón E,
- Ordóñez A,
- López-Barneo J
- Sun XH,
- Ding JP,
- Li H,
- Pan N,
- Gan L,
- Yang XL,
- Xu HB
- Giangiacomo KM,
- Kamassah A,
- Harris G,
- McManus OB
- Sauzeau V,
- Le Jeune H,
- Cario-Toumaniantz C,
- Smolenski A,
- Lohmann SM,
- Bertoglio J,
- Chardin P,
- Pacaud P,
- Loirand G
- Liu Y,
- Hudetz AG,
- Knaus HG,
- Rusch NJ
Novelty and Significance
What Is New?
The first time that an antibacterial peptide was found downregulated in sera of patients with hypertension.
The first peptide opener of large-conductance Ca2+-activated potassium-mSlo+hβ1 channels was found.
Provides a new therapeutic target for the treatment of hypertension.
What Is Relevant?
There was a significant lower level of human β-defensin 2 (HBD2) in sera of patients with hypertension.HBD2 could significantly increase the currents of large-conductance Ca2+-activated potassium-mSlo+hβ1 channels, which play a vital role in hypertension.
HBD2 lowered blood pressures in monkeys and rats.
As a known immune molecule, HBD2 was found to activate large-conductance Ca2+-activated potassium-mSlo+β1 channels and to lower blood pressures in rats and monkeys. HBD2 may be a novel regulator of blood pressure and provides a new therapeutic target for the treatment of hypertension.