© 1997 American Heart Association, Inc.
Articles |
Decreased Expression of Kv4.2 and Novel Kv4.3 K+ Channel Subunit mRNAs in Ventricles of Renovascular Hypertensive Rats
From the Department of Pharmacology (K.T., D.L., K.M.H., E.S.L.) and the Center for Clinical Pharmacology (P.L., E.K.J.), University of Pittsburgh (Pa).
Correspondence to Edwin S. Levitan, E1351 Biomedical Science Tower, Department of Pharmacology, University of Pittsburgh, Pittsburgh, PA 15261. E-mail levitan{at}server.pharm.pitt.edu
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Abstract |
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Abstract Hypertension-induced cardiac hypertrophy is associated with alterations in ventricular action potentials. To understand molecular mechanisms underlying this electrical abnormality, expression of cardiac voltage-gated K+ channel subunit genes was examined in ventricles of renovascular hypertensive rats. While generating a rat Kv4.3 probe, we discovered a previously unreported 19–amino acid insertion in the C-terminal intracellular region of the channel subunit. RNase protection assays indicated that this novel isoform is predominant in rat lung and heart. Effects of renovascular hypertension were then determined by using renal artery clipping models: two-kidney, one clip (2K-1C) rats, a model of high-renin hypertension with a normal plasma volume, and one-kidney, one clip (1K-1C) rats, a model of normal renin with a raised plasma volume. Expression of Kv4.2 and Kv4.3 mRNAs was diminished by >50% in ventricles of 2K-1C rats; however, no changes in the expression of Kv1.2, Kv1.4, Kv1.5, Kv2.1, or KvLQT1 mRNAs were detected. Similar downregulation of Kv4.2 and Kv4.3 mRNAs was detected in 1K-1C rats. Chronic administration of captopril, an angiotensin-converting enzyme inhibitor, blocked the development of hypertension and the suppression of Kv4 subfamily channel mRNA expression in 2K-1C rats. Furthermore, captopril administration to sham-operated rats significantly increased Kv4.2 mRNA. These results indicate that renovascular hypertension causes specific reductions in Kv4 subfamily channel mRNA expression and that this effect is likely to be mediated primarily by an increase in cardiac afterload.
Key Words: K+ channel • alternative splicing • transient outward current • renovascular hypertension • ventricular hypertrophy
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Introduction |
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Systemic hypertension is associated with various heart diseases.1 2 3 Cardiac hypertrophy is both a major adaptive response to pressure overload and an important risk factor in patients with hypertension. Hypertrophied myocytes in experimental model animals as well as in human patients usually exhibit prolongation of action potential duration.4 A variety of ionic current mechanisms have been proposed to contribute to this effect. For example, alterations in L-type Ca2+ current density and/or kinetics have been observed in hypertrophied ventricles secondary to renovascular hypertension.5 6 Likewise, inward rectifier K+ current density in ventricular myocytes is decreased in genetically hypertensive rats.7 Finally, many studies have shown decreases in Ito density.8 9 10 11 12 13 14 For instance, a chronic increase in pressure load produced by abdominal aortic ligation significantly reduced macroscopic Ito density in rat ventricular myocytes8 9 by a mechanism not involving changes in single-channel unitary conductance or open probability.8 Likewise, hypertrophied ventricular myocytes secondary to pulmonary artery constriction,10 deoxycorticosterone acetate/salt–induced hypertension,11 genetically determined hypertension,12 increased growth hormone secretion,13 or myocardial infarction14 have also shown significant decreases in Ito density. Since Ito is important for early repolarization, a smaller Ito might have a large impact on the ventricular action potential waveform.
Molecular biological studies have identified a large number of
voltage-gated K+ channel pore-forming 
subunits that
could contribute to Ito and other voltage-gated
K+ currents in rat hearts.15 16 17 18 19 These
include the Kv1.1, Kv1.2, Kv1.4, Kv1.5, Kv2.1, Kv4.2, Kv4.3,
KvLQT1, and erg genes. Several attempts have been made to
correlate channel subunit genes expressed to native
Ito seen in myocytes. For example, heterologous
expression of Kv4.2 or Kv4.3 mRNA generates channels with kinetics and
pharmacological properties similar to Ito in
cardiac myocytes.18 20 21 22 Furthermore, Kv4.2 mRNA and
Ito are similarly expressed in a gradient across
the left ventricular wall.15 Therefore, Kv4.2
and Kv4.3 subunits likely contribute significantly to
Ito in rat ventricular myocytes.
Ito might also be produced by Kv1 subfamily
-ß subunit complexes.23 24 25 Thus, many channel subunit
genes might participate in forming hypertension-sensitive
Ito channels.
Recent studies involving the regulation of cardiac voltage-gated K+ channel expression raise the possibility that the reduction in Ito might be due to inhibition of K+ channel gene expression. We have demonstrated that glucocorticoid hormones upregulate expression of the Kv1.5 gene in neuroendocrine26 27 and cardiac cells.28 29 This transcriptional activation of the gene leads to increases in channel protein and activity.26 28 Moreover, expression of K+ channel transcripts is also found to be altered in diseased hearts.30 31 In genetically determined and renovascular hypertensive rat ventricles, RT-PCR analyses suggested that Kv1.4 and Kv1.5 mRNAs were increased and decreased, respectively.31 Furthermore, a recent report indicates that Kv2.1 and Kv4.2 mRNAs and proteins are reduced in remodeled ventricles after experimental myocardial infarction.30 Hence, altered expression of K+ channel genes may be involved in long-term control of cardiomyocyte electrical properties.
In the present study, we examined the effects of hypertension on expression of cardiac K+ channel mRNAs using two well-established renovascular hypertensive models: 2K-1C and 1K-1C rats. We show that renovascular hypertension dramatically and specifically downregulates the expression of transcripts for the two Kv4 subfamily channel genes in ventricles of rat heart. We also report the identification of a novel splicing variant of Kv4.3 transcripts that is abundantly expressed in rat cardiovascular tissues.
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Materials and Methods |
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RT-PCR and Subcloning of Rat KvLQT1 and Kv4.3 cDNAs
A partial rat KvLQT1 cDNA was obtained by RT-PCR with the following oligonucleotides: 5'-CGGGATCCTGGTCTGC CTCATCTTCAG-3', which includes a part of the published partial human KvLQT1 cDNA32 (nucleotides 14 to 33) and the underlined sequence, and 5'-TTGTCTTTGTCCAGCTTGA- 3', which corresponds to the human sequence 882 to 900. Briefly, first-strand cDNA was made with
1 µg total
RNA isolated from rat heart using the 3' end
oligonucleotide as a primer.33 PCR was
performed with the first-strand cDNA and 1-pmol/µL primers in
a 50-µL reaction using Taq polymerase under the following conditions:
94°C for 2 minutes, 58°C for 1 minute, and 72°C for 2 minutes+20
s/cycle for 30 cycles. The 900-bp PCR product was purified and
subcloned into T-vector (Promega). Sequencing of the obtained
clones revealed high similarity of the rat KvLQT1 sequences (GenBank
accession No. U92665) to the human32 34 35 and
mouse35 counterparts.
To obtain rat Kv4.3 cDNA, oligonucleotides with
the sequences 5'-GAGCTGACCGGCACCCCA-3' and
5'-TGTTTTGCAGTTTGGTCTCAGTC-3', corresponding to parts of the
C-terminal intracellular region of rat Kv4.3 cDNA18
(nucleotides 1421 to 1438 and 1800 to 1822), were used for
RT-PCR under conditions identical to those used in the preparation of
rat KvLQT1 cDNA, except for annealing temperature at 56°C. RT-PCR
with random-primed or oligo d(T)–primed first-strand cDNA
(first-strand cDNA synthesis kit, Clontech) made with rat heart RNA
consistently produced small and large amounts of DNA with
400 and 460 bp, respectively. The short and long PCR products
were cloned into T-vector and sequenced. The long product contained
a previously unreported 19–amino acid insertion in the C-terminal
region of channel peptide (GenBank accession No. U92897).
Preparation of Renovascular Hypertensive Rats
2K-1C and 1K-1C Goldblatt hypertensive rats represent
two distinct forms of renovascular hypertension with different causes
of high blood pressure. The 2K-1C rat represents a high-renin
form of hypertension with a normal plasma volume.36 In
contrast, the 1K-1C rat represents a normal renin form of
hypertension with raised plasma volume.36
In order to generate these two models of experimental animals, 10-week-old male Sprague-Dawley rats (Sasco Inc, Omaha, Neb) were anesthetized with pentobarbital (50 mg/kg). A silver clip (0.254-mm gap) was permanently installed (2K-1C and 1K-1C rats) or temporarily placed and removed (sham-operated rats) on the left artery. In 2K-1C and corresponding sham-operated animals, the right kidney was not disturbed, whereas in 1K-1C and corresponding sham-operated animals, the right kidney was removed. Animals were allowed free access to food and drinking water. Some animals received captopril in their drinking water (0.8 mg/mL).
Seven weeks after clipping or sham clipping, the animals were prepared for hemodynamic measurements. Rats were anesthetized with sodium thiobutabarbital (Inactin, Research Biochemicals Int; 100 mg/kg IP) and placed on a Deltaphase isothermal pad (Braintree Scientific, Inc). Body temperature was monitored with a digital rectal probe thermometer (Physiotemp Instruments, Inc) and maintained at 37°C by adjusting a heat lamp above the animal.
The trachea was cannulated with a PE-240 catheter to facilitate respiration, and a PE-50 catheter was placed in the left carotid artery and attached to a Micro-Med digital blood pressure analyzer (Louisville, KY) for continuous monitoring of arterial blood pressure and heart rate at 1100 Hz. After a 45-minute rest period, arterial blood pressure and heart rate were time-averaged for 30 minutes, and then 1 mL of blood was removed from the carotid artery. The arterial blood samples were quickly centrifuged, and the plasma was frozen at -40°C until assayed for renin activity using a commercially available kit (DuPont Medical Products). The hearts were quickly removed, and the atria and ventricles were rapidly separated and frozen on dry ice.
RNase Protection Assays
Portions of rat K+ channel cDNAs were subcloned into
pBluescript KS(+) (Strategene) as templates for RNA probe synthesis:
Pvu II–Sac I fragment of Kv1.237
(nucleotides 519 to 1032), Pst I–Xba
I fragment of Kv1.437 (nucleotides 1922
to 2365), Bam HI–Pst I fragment of
Kv2.138 (nucleotides 1537 to 2114), 5' end
EcoRI-HindIII fragment of Kv4.215
(nucleotides 1 to 539), and Sma
I–Kpn I fragment of Kv4.318
(nucleotides 58 to 777). A template for Kv1.5 RNA probe
synthesis was prepared by Xba I digestion of
pKv1.5/pGEMA,39 as described previously.26
Analysis of Kv4.3 splicing was done with RNA probe containing
the whole sequence of the cDNA clone with the insertion obtained by
RT-PCR in the present study (see Fig 1A
). A template for KvLQT1 RNA probe
synthesis was made by internal Dde I digestion of a partial
rat cDNA clone obtained as described above.
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Total RNA was isolated from whole ventricles by acid phenol guanidine thiocyanate extraction,40 and RNA concentration was determined spectrophotometrically using absorbance at 260 nm of 40 µg/mL. Total RNA (10 µg) was hybridized with one of the K+ channel and cyclophilin RNA probes, which were digested with RNases, and protected RNAs were recovered and separated on denaturing polyacrylamide gel, as described previously.26 28 K+ channel mRNA levels were determined by measuring the intensity of signals by using a PhosphorImager (Molecular Probes), followed by normalizing data with cyclophilin mRNA level as an internal control.
The KvLQT1 mRNA level appeared to be comparable to that of Kv4.2 or Kv4.3 mRNA, which has been reported to be the most abundant among all the known Kv mRNAs expressed in rat heart.16 18
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Identification and Tissue Distribution of a Novel Kv4.3 Splicing Variant
To obtain a partial Kv4.3 cDNA as a template for RNA probe synthesis, we used RT-PCR with rat heart RNA. RT-PCR with one set of primers corresponding to a portion of the C-terminal intracellular region of rat Kv4.3 cDNA16 (nucleotides 1421 to 1822) produced two fragments with distinct sizes: the larger fragment was much more abundant; however, its size (
460 bp) was
significantly larger than expected (400 bp). RT-PCR with random
hexamer– or oligo d(T)–primed first-strand cDNA made with lung,
atrium, or right or left ventricular RNA
consistently amplified an 460-bp product. In contrast,
RT-PCR with the same primers and total brain RNA yielded equal amounts
of 400- and 460-bp DNA fragments. Subcloning and sequencing of
the PCR fragments indicate that the long fragment contains an
additional nucleotide sequence (Fig 1A
). Sequence alignment
reveals the presence of an alternatively spliced Kv4.3 transcript with
a previously unreported in-frame 19–amino acid insertion (Fig 1A).
Since our RT-PCR detected the long DNA fragment with the
insertion in several cardiovascular tissues, we
determined whether this splicing variant might be abundant in these
tissues. To test this possibility, an RNase protection assay was
designed to measure separately the long and short splicing isoforms
(Fig 1B). Two protected fragments with sizes expected from the long and
short isoforms are seen in total brain RNA. The long isoform is also
significant in many other tissues, such as anterior pituitary, lung,
atrium, and right and left ventricles, whereas the short isoform is
less evident or undetectable in these tissues. PhosphorImager
quantification of the signals for the long and short isoforms indicates
that the long form is 4-fold more abundant than the short form in
the atria and right ventricle and 
10-fold more abundant in the left
ventricle. These results indicate that the splicing isoform of Kv4.3
with the 19–amino acid insertion is predominant in the rat
cardiovascular tissues.
Renovascular Hypertension Decreases Kv4.2 and Kv4.3 mRNAs
Effects of renovascular hypertension on K+
channel subunit mRNA levels were examined using 2K-1C rats, a model of
high-renin renovascular hypertension. Some of the 2K-1C and
sham-operated animals were given the angiotensin-converting
enzyme inhibitor captopril in their drinking water (0.8
mg/mL) beginning immediately after clipping or sham clipping.
Seven weeks after clipping, all the 2K-1C animals given regular water
developed mean arterial blood pressures (>190 mm Hg)
higher than those found in the sham-operated rats (<140 mm Hg)
(Table). Chronic administration of
captopril lowered the mean blood pressure of 2K-1C and sham-operated
rats compared with the corresponding groups of rats given regular water
(Table). RNase protection assays were then used to measure
K+ channel mRNAs in total RNA isolated from the ventricles
of these animals. Transcripts for the two Kv4 subfamily genes, Kv4.2
and Kv4.3, significantly decreased in the ventricles of 2K-1C rats
compared with sham-operated rat ventricles (P<.01,
two-tailed t test, n=3 for each group), and this effect was
blocked by the administration of captopril (Fig 2). Administration of captopril to
sham-operated rats also significantly increased Kv4.2 mRNA levels
(P<.05, two-tailed t test, n=3 for each group)
and tended to increase Kv4.3 mRNA (Fig 2). The two splicing isoforms of
Kv4.3 mRNA were similarly changed by these treatments (data not shown).
No significant changes in the expression of Kv1.2, Kv1.4, Kv1.5, Kv2.1,
or KvLQT1 mRNA were seen with renal artery clipping and/or
administration of captopril (Fig 3).
Thus, renovascular hypertension specifically decreases expression of
the two Kv4 subfamily channel mRNAs.
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The detected decrease in the two Kv4 subfamily channel transcripts
might be due to hemodynamic factors (ie, increased
cardiac afterload). Alternatively, activation of the
renin-angiotensin system might directly decrease in
ventricular channel mRNA levels independent of blood
pressure. To examine the last possibility, we measured Kv4.2 and Kv4.3
mRNA levels in the ventricles of 1K-1C rats, a model of normal renin
renovascular hypertension (Fig 4). The
mean arterial blood pressure was higher in all the 1K-1C
rats (>190 mm Hg) than in the sham-operated rats (<140
mm Hg) (Table). Plasma renin activity was not significantly
(P=.8) elevated in 1K-1C rats (20±7 ng AI ·
mL-1 · h-1,
n=5) compared with sham-operated rats (7±1 ng AI ·
mL-1 · h-1,
n=6, 2K-1C sham and 1K-1C sham groups combined). In contrast, the 2K-1C
rats developed significantly (P<.05) higher plasma renin
activity (89±32 ng AI · mL-1 ·
h-1, n=3). RNase protection assays revealed
that the expression of Kv4.2 and Kv4.3 mRNAs was significantly
decreased in the ventricles of 1K-1C rats (P<.05, n=5 for
1K-1C and n=3 for sham-operated groups). Thus, renovascular
hypertension–induced decreases in Kv4 subfamily channel mRNAs are
likely to be mediated primarily by increases in cardiac afterload.
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Tissue-Specific Splicing of Kv4.3 mRNA
The diversity of cardiac voltage-gated K+ channels largely arises from expression of multiple channel subunit genes, combinations of these subunits in terameric assembly, and association with accessory subunits. In the case of Kv3 subfamily channel subunits, alternative splicing also contributes to the production of channel diversity.41 42 43 In the present study, we used RT-PCR and RNase protection assays to identify a novel Kv4.3 splicing variant, reporting the first case of splicing for mammalian Kv4 subfamily channel subunits. This splicing product contains a previously unreported 19–amino acid insertion in the C-terminal intracellular region. Our results also indicate that the novel Kv4.3 isoform with the insertion is abundant in many tissues. These include pituitary, lung, atrium, and right and left ventricles. Thus, splicing of Kv4.3 transcripts is tissue specific and may contribute to the diversity of Ito channels in a variety of cell types.
Regulation of Kv4 Subfamily Channel Gene Expression by
Renovascular Hypertension
The present study demonstrates that renovascular hypertension
dramatically and specifically downregulates expression of
ventricular Kv4.2 and Kv4.3 mRNAs. Heterologous expression
of Kv4.2 or Kv4.3 produces channels with properties similar to
Ito in cardiac myocytes: the current
inactivates during depolarization and is sensitive to
4-aminopyridine and flecainide but not to
tetraethylammonium.17 18 20 21
Moreover, Kv4.2 mRNA is expressed in a gradient across the left
ventricular wall, which correlates well with
Ito density.15 Therefore, Kv4.2
homomeric and/or Kv4.2-Kv4.3 heteromeric channels are likely to
contribute significantly to Ito in rat
ventricle. Hence, the present study suggests that renovascular
hypertension may decrease Ito density by
reducing the expression of Kv4.2 and Kv4.3 transcripts. The
downregulation of Kv4.2 mRNA expression may also change the
distribution of Kv4 channels across the left ventricular
wall and thus affect the gradient in Ito
density.
The present study also indicates that the downregulation of Kv4
subfamily channel transcripts is less likely to be mediated by
activation of the renin-angiotensin system and may occur in
response to changes in cardiac afterload. The former conclusion is
supported by the finding that the percentage reduction in Kv4 subfamily
channel mRNAs was similar in 2K-1C and 1K-1C renovascular hypertensive
rats, whereas plasma renin activity was markedly elevated (>10-fold)
in 2K-1C rats and not statistically significantly changed in 1K-1C
rats. A role for arterial blood pressure in the control of
Kv4 subfamily channel gene expression is suggested by the observations
that captopril prevented both the development of hypertension and the
reduction of Kv4 subfamily channel mRNAs in 2K-1C rats and that
captopril lowered arterial blood pressure and increased Kv4
subfamily channel mRNAs in sham-operated rats. The present data do
not exclude the possibility of an interaction between the
renin-angiotensin system and arterial blood
pressure. For example, it is conceivable that normal levels of renin
are required to condition the myocytes to respond to elevations in
arterial blood pressure to reduce Kv4 subfamily channel
mRNA expression. It is also possible that 2K-1C and 1K-1C rats have
another metabolic and/or hemodynamic
abnormality besides arterial hypertension in common that
mediates the reduction in Kv4 subfamily channel mRNA expression.
Finally, our results do not differentiate between direct action of
increases in pressure load and effects secondary to
hypertension-induced hypertrophy to decrease the channel
mRNA expression. In previous experiments, we have observed that the
heart weight–to–body weight ratio increased by 15% at 4 weeks
after clipping in the 2K-1C rats compared with sham-operated rats
(authors' unpublished data, 1996). A similar increase in the heart
weight–to–body weight ratio was also obtained in the 1K-1C animals.
Thus, it is certainly possible that the reduction in the channel mRNA
expression might be secondary to hypertension-induced
hypertrophy. Hence, future studies are needed to determine
if arterial pressure changes are necessary and sufficient
for the downregulation of Kv4 subfamily channel gene expression.
Comparison With Other Studies on K+ Channel Subunit
Gene Expression in Hypertrophied Hearts
Two previous studies have also examined K+ channel
subunit gene expression in hypertrophied ventricles.30 31
An earlier study used RT-PCR assays to examine Kv1.4 and Kv1.5 mRNA
levels in genetically determined and 2K-1C renovascular hypertensive
rat ventricles.30 In contrast to the present results,
changes in Kv1.4 and Kv1.5 mRNAs were reported in ventricles of 2K-1C
rats. We also found no significant change in Kv1.4 or Kv1.5 mRNA in
1K-1C rat ventricles (data not shown). One possible explanation for the
different results is that the detected changes in Kv1.4 and Kv1.5 mRNAs
in the previous study might be due to effects other than hypertension
or hypertension-induced hypertrophy. Kv1.4 and Kv1.5 mRNA
levels are rapidly and dramatically regulated in response to many
distinct stimuli.28 29 44 Thus, it is possible that the
observed changes in Kv1.4 and/or Kv1.5 mRNA levels might be mediated by
other stimuli (eg, stress). Alternatively, the different assays used in
the two studies may be important. The present study examined
expression of multiple subfamily channel mRNAs with RNase protection
assays. This methodology is considered to be a more quantitative and
reliable approach for measuring mRNA expression. Indeed, the
consistent and specific decrease in Kv4, but not other
subfamily, channel mRNAs in both 2K-1C and 1K-1C rat ventricles argues
against experimental artifacts associated with measurements. Hence, we
suggest that renovascular hypertension–induced changes in Kv1.4
and Kv1.5 transcripts are relatively minor compared with the
downregulation of Kv4 subfamily channel mRNAs.
A second report showed that Kv2.1 and Kv4.2 mRNAs are reduced in remodeled ventricles after experimental myocardial infarction.31 The fact that renovascular hypertension in our experiments failed to decrease Kv2.1 transcript suggests that the etiology of hypertrophy may affect Kv2.1 gene expression. However, it is unknown whether this is the case for Kv4.3 gene expression, since its message was not measured in the previous study. It is possible that reduction in Kv4 subfamily channel mRNA levels may be a common alteration seen in hypertrophied ventricles.
Conclusions
There has been accumulating evidence suggesting that
K+ channel expression is a target for long-term control of
excitability by physiological stimuli. In addition,
K+ channel expression may be altered with disease. In the
present study, we demonstrated that Kv4 subfamily channel mRNAs are
lowered in ventricles of renovascular hypertensive rats. It has been
shown that cardiac hypertrophy secondary to systemic
hypertension is associated with increases in the incidence of sudden
death and cardiac morbidity.1 2 3 The electrical abnormality
seen in hypertrophied myocytes may be in part responsible for these
pathological manifestations. The specific decreases in Kv4.2 and novel
Kv4.3 channel transcripts may significantly influence action potential
waveforms, and this alteration may be region specific. Hence, the
downregulation of Kv4 subfamily channel gene expression may contribute
to the pathophysiological changes associated with
ventricular hypertrophy.
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Acknowledgments |
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This study was supported by National Institutes of Health grant HL-55312 (to Dr Levitan) and grants HL-35909 and HL-55314 (to Dr Jackson) and a Grant-in-Aid from the American Heart Association, Pennsylvania Affiliate, Inc (to Dr Levitan). Dr Levitan is an Established Investigator of the American Heart Association. We thank Dr M. Tamkun for rat Kv1.2, Kv1.4, and Kv4.2 cDNAs and Drs D. McKinnon and J. Dixon for rat Kv4.3 cDNA. The nucleotide sequences reported in this study have been submitted to the GenBank/EMBL Data Bank with accession Nos. U92655 (rKVLQT1) and U92897 (rKv4.3b).
Received January 23, 1997; accepted June 26, 1997.
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