Published online before print November 24, 2008, doi: 10.1161/HYPERTENSIONAHA.108.116947
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(Hypertension. 2009;53:70.)
© 2009 American Heart Association, Inc.
Original Articles |
Increased Transient Receptor Potential Canonical Type 3 Channels in Vasculature From Hypertensive Rats
From the Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension (D.L., D.Y., H.H., X.C., T.C., X.F., L.M., Z.L., L.W., Z.Y., Z.Z.) Chongqing, PR China; and Med. Klinik, Charite Campus Benjamin Franklin (M.T.) Berlin, Germany.
Correspondence to Dr Zhiming Zhu, Department of Hypertension and Endocrinology, Daping Hospital, Third Military Medical University, Chongqing, PR China. E-mail zhuzm{at}yahoo.com or Dr Daoyan Liu, Department of Hypertension and Endocrinology, Daping Hospital, Third Military Medical University, Chongqing, PR China. E-mail zhuzm@yahoo.com
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Abstract |
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We tested the hypothesis that transient receptor potential canonical type 3 (TRPC3) channels are increased in vascular smooth muscle cells and aortic tissue from spontaneously hypertensive rats (SHR) compared with normotensive Wistar Kyoto rats. Expression of TRPC3 was analyzed by immunohistochemistry and Western blotting. TRPC3 gene knockdown was performed by specific small interfering RNA and TRPC3 overexpression using the pAdEasy-1 system. Cytosolic calcium was measured using fluorescence spectrophotometry and vasoconstriction of aortic rings using a force transducer. In SHR, the expression of TRPC3 channel protein was significantly higher in aortic rings (1.48±0.05 versus 1.00±0.06; each n=6; P<0.01) and vascular smooth muscle cells (1.28±0.08 versus 1.00±0.03; each n=6; P<0.05) compared with Wistar Kyoto rats. Knockdown of TRPC3 gene expression by specific small interfering RNA significantly reduced the angiotensin II–induced calcium influx by 30±3% (n=6; P<0.01), whereas TRPC3 overexpression significantly increased it by 55±3% (n=6; P<0.01). The angiotensin II–induced calcium increase was significantly enhanced in vascular smooth muscle cells from SHR compared with Wistar Kyoto rats, even in the presence of the calcium channel blocker amlodipine. Angiotensin II significantly elevated the TRPC3 channel protein expression in vascular smooth muscle cells from SHR from 1.28±0.08 to 1.61±0.08 (each n=6; P<0.01). Angiotensin II–induced TRPC3 expression was prevented by telmisartan. Administration of telmisartan to SHR for 4 weeks significantly reduced blood pressure, angiotensin II–induced vasoconstriction, and TRPC3 channel protein expression in aortic tissue. TRPC3 expression was not significantly reduced after reduction of blood pressure in SHR using amlodipine. In conclusion, we give experimental evidence that increased TRPC3 channel protein expression in the vasculature is important for elevated blood pressure.
Key Words: transient receptor potential canonical channel type 3 • calcium • spontaneously hypertensive rats
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Introduction |
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Transient receptor potential canonical (TRPC) are nonselective cation channels that had been identified in several tissues, including heart and vascular smooth muscle cells (VSMC). TRPC type 3 (TRPC3) channels play an important role in several cardiovascular diseases and probably hypertension.1–10 An increased TRPC3 expression could be demonstrated in peripheral monocytes from spontaneously hypertensive rats (SHR) compared with normotensive Wistar Kyoto rats (WKY).5,6 Dietrich et al reported that TRPC6 knockout mice showed elevated TRPC3 channel expression, increased vasoconstriction, and increased blood pressure.7 Increased angiotensin II–induced vasoconstriction and proliferation of VSMC, as well as augmented angiotensin II–induced intracellular signal transduction pathways and calcium influx, have frequently been observed in primary hypertension.6,11–15 Part of the action of angiotensin II may occur through TRPC channels. Although data from the literature gave evidence that calcium influx through TRPC3 channels may contribute to vasoconstriction and hypertension, this has not been tested yet using VSMC from SHR. In the present study, we tested the hypothesis that calcium influx through TRPC3 is increased in VSMC and aortic tissue from SHR compared with WKY.
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Methods |
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A detailed description of the Methods can be found in an online supplement available at http://hyper.ahajournals.org.
Animals (SHR and WKY), interventions and hemodynamic measurements, preparation of aortic rings and vasoconstriction,16,17 culture of VSMC, measurements of cytosolic calcium concentration,18,19 RNA isolation and RT-PCR, and immunoblottings and immunohistochemistry had been described previously by our group. All experiments were performed as approved by the animal care and use committee. The TRP channel blocker SKF-96365 (Merck Biosciences; final concentration 10 µmol/L) was used.20–22 Changes of cytosolic calcium were reported as described.23 Antibodies were purchased from Alomone Labs (Jerusalem, Israel),5,24,25 or Santa Cruz Biotechnology (Santa Cruz, Calif). Small interfering RNA knockdown was performed using silencer small interfering RNA transfection kit (Ambion; Austin, Tex). Overexpression of TRPC3 channels was done using pAdEasy-1 system.
Statistical Analysis
All results are expressed as the mean±SEM of 
3 independent experiments. Data were compared using 2-tailed Student t test or ANOVA and Tukey’s multiple comparisons post hoc test as appropriate. Two-sided P values <0.05 were considered significant. Where error bars do not appear on the figures, error was within the symbol size.
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Results |
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Identification of TRPC in the Vasculature
First, we used RT-PCR to show the presence of TRPC3 transcripts in vasculature from adult normotensive WKY, 5-week-old prehypertensive SHR (preSHR), and adult SHR. Calculating the TRPC3/GAPDH ratio indicated that TRPC3 transcripts were significantly more expressed in vasculature from adult SHR compared with adult WKY or preSHR (each P<0.05; Figure 1A).
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Second, we identified TRPC3 channel proteins in VSMC from SHR and normotensive WKY using specific antibodies and immunohistochemistry (Figure 1B).
Increased Expression of TRPC3 Channel Protein in Aortic Tissue From SHR
Systolic blood pressure was 196±6 mm Hg in adult SHR and 109±4 mm Hg in adult WKY (each n=6; P<0.05). Body weight was 329±13 g in SHR and 326±11 g in WKY. The expression of TRPC3 channel protein was significantly elevated in aortic tissue (1.48±0.05 versus 1.00±0.06; each n=6; P<0.01; Figure 2A) from SHR compared with WKY. In contrast, the expression of angiotensin II type 1 receptor (AT1R) protein was not significantly different in aortic rings from SHR and WKY (1.13±0.03 versus 1.00±0.06; each n=6; P=NS; Figure 2B).
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Increased Expression of TRPC3 Channel Protein in VSMC From SHR
The expression of TRPC3 channel protein was significantly elevated in VSMC from SHR compared with WKY (1.28±0.08 versus 1.00±0.03; each n=6; P<0.05; Figure 2C). In contrast, the expression of AT1R protein was not significantly different in VSMC from SHR and WKY (1.14±0.06 versus 1.00±0.05; each n=6; P>0.05; Figure 2D). In additional experiments, we established that TRPC3 channel protein expression was not affected by cell culture by comparing TRPC3 channel protein expression in freshly isolated cells and cultured VSMC from the third and tenth passage. As shown in Figure 2E for WKY (freshly isolated cells 1.05±0.12; third passage 1.09±0.05; tenth passage 1.06±0.06; each n=3; P=NS) and Figure 2F for SHR (freshly isolated cells 1.22±0.10; third passage 1.27±0.07; tenth passage 1.21±0.11; each n=3; P=NS), TRPC3 channel protein expression was not affected by cell culture.
As indicated in Figure 2G and 2H, both systolic blood pressure and the expression of TRPC3 channel protein in aortic tissue from adult SHR were significantly higher compared with 5-week-old preSHR or with adult WKY.
Now, we investigated whether the increased TRPC3 channel protein expression in SHR was associated with enhanced angiotensin II–induced elevation of blood pressure, vasoconstriction, and calcium increase in SHR. The intravenous injection of angiotensin II at a rate of 24 µg/kg per hour for 60 minutes increased mean arterial blood pressure in rats. The angiotensin II–induced elevation of arterial blood pressure was significantly higher in SHR compared with WKY (53±3 mm Hg versus 22±4 mm Hg; each n=6; P<0.05).
Furthermore, angiotensin II–induced aortic contraction was significantly higher in SHR compared with WKY (82±3% of maximal potassium contraction versus 54±6% of maximum potassium contraction; each n=6; P<0.01). Additional experiments showed that compared with control conditions (100±8%; n=12), the administration of calcium channel blocker amlodipine significantly reduced the angiotensin II–induced contraction to 72±7% (n=9; P<0.05), whereas the administration of TRP cation channel blocker SKF-96365 significantly reduced it to 18±3% (n=7; P<0.05 by ANOVA and Tukey’s multiple comparisons post hoc test; Figure 3A). As indicated in Figure 3A, the angiotensin II–induced aortic contraction was also significantly higher in SHR compared with WKY in the presence of amlodipine but not in the presence of SKF-96365.
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Baseline cytosolic calcium concentration was similar in VSMC from SHR and WKY (103±12 versus 99±9 nmol/L, respectively; each n=6; P=NS).
The angiotensin II–induced calcium increase was significantly enhanced in VSMC from SHR compared with WKY (increase of cytosolic calcium 229±10 versus 115±13 nmol/L, respectively; P<0.01). In the presence of calcium channel blocker amlodipine, the angiotensin II–induced calcium influx was still significantly higher in VSMC from SHR compared with WKY (170±10 versus 130±12 nmol/L, respectively; P<0.01). In contrast, in the presence of the TRP cation channel blocker SKF-96365, the angiotensin II–calcium-influx was similar in VSMC from SHR and WKY (126±13 versus 113±10 nmol/L, respectively; P=NS by ANOVA and Tukey’s multiple comparisons post hoc test; Figure 3B).
Using TRPC3 channel protein overexpression, we confirmed that an increased TRPC3 channel protein expression in VSMC caused elevated angiotensin II–induced calcium influx, whereas TRPC3 gene knockdown in VSMC reduced TRPC3 expression and caused reduced angiotensin II–induced calcium influx. Transfecting TRPC3 gene into cultured VSMC from SHR significantly increased TRPC3 channel protein expression from 100±4% to 167±4% (n=6; P<0.01; Figure 4A) and hence significantly elevated the angiotensin II–induced calcium increase by 55±4% (n=6; P<0.01; Figure 4B).
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Specific small interfering RNA against TRPC3 significantly reduced TRPC3 channel protein expression in cultured VSMC from SHR from 100±11% to 49±4% (n=3; P<0.05; Figure 4C), whereas TRPC6 channel protein expression was not affected (100±18% versus 99±16%; P=NS; Figure 4D). The reduction of TRPC3 channel protein expression in VSMC significantly reduced the angiotensin II–induced calcium increase by 36±3% (n=5; P<0.05; Figure 4E).
Next, we determined whether angiotensin directly increases the expression of TRPC3 channel protein in VSMC. To this end, VSMC from SHR or WKY were cultured in the continuous presence of 100 nmol/L angiotensin II throughout culturing. The administration of angiotensin II significantly elevated the expression of TRPC3 channel protein in VSMC from SHR from 1.28±0.08 to 1.61±0.08 (each n=6; P<0.01) but only slightly changed TRPC3 channel protein expression in VSMC from WKY from 1.00±0.03 to 1.11±0.07 (each n=6; P=NS; Figure 5A). As indicated in Figure 5B, the administration of the AT1R antagonist telmisartan prevented the angiotensin II–induced TRPC3 channel protein expression in VSMC from SHR (0.74±0.05 versus 1.61±0.08; each n=6; P<0.01).
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These data indicated that angiotensin II increased the expression of TRPC3 channel protein in VSMC from SHR in vitro, and this effect could be blocked by the AT1R antagonist telmisartan. Now, we investigated whether the effects of telmisartan on TRPC3 channel protein expression could also be observed in vivo. To support the hypothesis that blocking of angiotensin II but not reduction of blood pressure per se affects TRPC3 channel protein expression in VSMC, we also used the calcium channel blocker amlodipine in SHR. SHR were randomly allocated to placebo, telmisartan (5 mg/kg per day), or amlodipine (10 mg/kg per day), which was administered for 4 weeks. Compared with placebo (201±5 mm Hg; n=6), the administration of telmisartan significantly reduced blood pressure to 124±8 mm Hg (n=6), whereas amlodipine significantly reduced blood pressure to 116±5 mmHg (n=5; each P<0.01 compared with placebo by ANOVA and Tukey’s multiple comparisons post hoc test; Figure 6A). Furthermore, the angiotensin II–induced vasoconstriction of aortic rings was significantly lower in the telmisartan group compared with the placebo group (30±8% versus 82±3%; each n=6; P<0.01). Most important, compared with placebo, telmisartan significantly reduced TRPC3 channel protein expression from 1.00±0.07 to 0.32±0.20 (each n=3; P<0.05 by ANOVA and Tukey’s multiple comparisons post hoc test), whereas TRPC3 channel protein expression was unchanged in the amlodipine group (1.30±0.15; n=3; P=NS; Figure 6B).
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Discussion |
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This report is the first to give experimental evidence for the importance of increased TRPC3 channel protein expression in the vasculature for elevated blood pressure in SHR. Foremost, for the first time, our present study showed an increased TRPC3 channel protein expression in the vasculature from adult SHR compared with adult WKY. In line with these findings, we observed increased TRPC3 transcripts in the vasculature from SHR compared with WKY. Furthermore, we showed that TRPC3 channel protein expression in the vasculature from 5-week-old prehypertensive SHR was similar to normotensive WKY. Second, for the first time, this study reported that TRPC3 channel proteins are regulated by angiotensin II in VSMC from SHR. Third, for the first time, this study showed that the long-term administration of telmisartan (but not amlodipine) to hypertensive rats reduces TRPC3 channel protein expression, confirming the importance of TRPC3 channel protein regulation by angiotensin II in vivo as well. However, additional electrophysiological data are needed to support these results.
The increased expression of TRPC3 was associated with enhanced angiotensin II–induced elevation of blood pressure, enhanced angiotensin II–induced vasoconstriction, and enhanced angiotensin II–induced calcium influx in VSMC from SHR. The hyper-responsiveness of vessels and VSMC from SHR after angiotensin II stimulation has been demonstrated clearly by several groups.6,12–15 Our present findings support previous results from several groups showing an increased angiotensin II–induced calcium influx in VSMC from SHR.12–15 Although major calcium influx in VSMC is mediated by voltage-gated calcium channels, TRPC channels are important signal transducers for agonist-mediated vascular contractility. It should be noted that the increased angiotensin II–induced calcium influx in primary hypertension could also be observed in the presence of the calcium channel blocker amlodipine. On the other hand, in the presence of the nonselective TRP cation channel blocker SKF-96365, the angiotensin II–induced calcium influx was similar in VSMC from SHR and WKY. Furthermore, in SHR, the angiotensin II–induced calcium influx was considerably more reduced in the presence of SKF-96365 compared with amlodipine, supporting an important role of calcium influx through TRP channels in SHR. Use of SKF-96365 has been validated to block TRP cation channels by several investigators.20–22 SHR is a well-known animal model of hypertension showing no significant differences of AT1R expression compared with WKY.26–28
We gave experimental evidence that TRPC3 channels are directly involved in angiotensin II–induced calcium influx. TRPC3 overexpression in VSMC increased the angiotensin II–induced calcium influx, whereas TRPC3 gene knockdown reduced angiotensin II–induced calcium influx in VSMC. In accordance with these results, Kaznacheyeva et al recently showed that downregulation of TRPC3 reduces calcium influx after depletion of intracellular stores in A431 cells.29 Second, the administration of angiotensin II significantly elevated the expression of TRPC3 in VSMC from SHR but not from WKY, supporting the proliferative action of angiotensin II in hypertension. Third, the administration of the AT1R antagonist telmisartan prevented the angiotensin II–induced elevation of TRPC3 expression in cultured VSMC from SHR in vitro. Long-term administration of telmisartan significantly reduced blood pressure, vasoconstriction, and most important, TRPC3 expression, in aortic tissue in vivo. On the other hand, we showed that the reduction of blood pressure using amlodipine did not significantly change TRPC3 expression in vasculature. In line with these results, Kogata et al reported that long-term treatment with telmisartan but not amlodipine improved the acetylcholine-induced vessel relaxation in hypertensive rats, although blood pressure reduction was similar in both groups.30 The observed reduction of TRPC3 after administration of telmisartan but not amlodipine may also explain in part the protective effects of AT1 antagonists in hypertension beyond blood pressure reduction as indicated by recent literature. The AT1 receptor antagonists irbesartan and candesartan but not amlodipine treatment showed beneficial effects in diabetic apolipoprotein E–null mouse or monkeys.31–32
Perspectives
We observed an increased TRPC3 cation channel expression in vasculature from SHR compared with WKY, which was associated with increased contraction, an increased angiotensin II–induced TRPC3 expression, and finally, the reduction of TRPC3 expression after administration of telmisartan but not amlodipine in vivo. These results add to a considerable body of evidence that TRP channels are involved in vasoregulatory mechanisms.33 Furthermore, the present results point to the relevance of TRPC3 in the pathogenesis of primary hypertension. As indicated by recent literature, expression of several TRP channel subtypes may be divergent and redundant in cardiovascular diseases. Moreover, TRP channels display diverse properties, localization, and regulation as a result of their assembly into distinct homomeric and heteromeric channel complexes.34 However, TRP channels will be fascinating targets to elucidate novel pathogenic mechanisms in hypertension, and TRP channels will be new therapeutic targets for cure of hypertension.
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Acknowledgments |
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Sources of Funding
This study was supported by grants 2006CB503905 and 2006CB503804 from 973 program (Z.Z.) and grant 30871058 from the National Natural Science Foundation of China (D.L.).
Disclosures
None.
Received May 25, 2008; first decision June 12, 2008; accepted November 3, 2008.
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