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Hypertension. 1995;25:1252-1259

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(Hypertension. 1995;25:1252-1259.)
© 1995 American Heart Association, Inc.

Articles

Angiotensin II Induces Cardiac Phenotypic Modulation and Remodeling In Vivo in Rats

Shokei Kim; Kensuke Ohta; Akinori Hamaguchi; Tokihito Yukimura; Katsuyuki Miura; Hiroshi Iwao

From the Department of Pharmacology, Osaka City University Medical School, Osaka, Japan.


*    Abstract
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 *Abstract
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Abstract Cardiac phenotypic modulation and remodeling appear to be involved in the pathophysiology of cardiac hypertrophy and heart failure. We undertook this study to examine whether angiotensin II (Ang II) in vivo, independent of blood pressure, contributes to cardiac phenotypic modulation and remodeling. A low dose (200 ng/kg per minute) of Ang II was continuously infused into rats by osmotic minipump for 24 hours or 3 or 7 days to examine the effects on the expression of cardiac phenotype–related or fibrosis-related genes. This Ang II dose caused a small and gradual increase in blood pressure over 7 days. Left ventricular mRNAs for skeletal {alpha}-actin, ß-myosin heavy chain, atrial natriuretic polypeptide, and fibronectin were already increased by 6.9-, 1.8-, 4.8-, and 1.5-fold, respectively, after 24 hours of Ang II infusion and by 6.9-, 3.3-, 7.5-, and 2.5-fold, respectively, after 3 days, whereas ventricular {alpha}-myosin heavy chain and smooth muscle {alpha}-actin mRNAs were not significantly altered by Ang II infusion. Ventricular transforming growth factor-ß1 and types I and III collagen mRNA levels did not increase at 24 hours and began to increase by 1.4-, 2.8-, and 2.1-fold, respectively, at 3 days. An increase in left ventricular weight occurred 3 days after Ang II infusion. Treatment with TCV-116 (3 mg/kg per day), a nonpeptide selective angiotensin type 1 receptor antagonist, completely inhibited the above-mentioned Ang II–induced increases in ventricular gene expressions and weight. Hydralazine (10 mg/kg per day), which completely normalized blood pressure, did not block cardiac hypertrophy or increased cardiac gene expressions by Ang II. This study demonstrates that Ang II in vivo, via the type 1 receptor, directly induces a shift to the fetal phenotype of cardiac myocytes and cardiac remodeling independent of blood pressure elevation. Thus, Ang II may play an important role in the modulation of cardiac performance in pathological cardiac hypertrophy.


Key Words: heart hypertrophy • actins • collagen • fibronectin • transforming growth factor-ß1 • receptors, angiotensin


*    Introduction
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 up arrowAbstract
 *Introduction
down arrowMethods
 down arrowResults
 down arrowDiscussion
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Cardiac hypertrophy is a major risk factor for heart failure in humans.1 2 Previous in vivo studies have shown that inhibitors of the renin-angiotensin system regress cardiac hypertrophy induced by hypertension,3 4 5 myocardial infarction,6 and aortic coarctation,7 thereby suggesting that angiotensin II (Ang II) may play a crucial role in the pathophysiology of cardiac hypertrophy. Furthermore, recent in vitro studies demonstrate that Ang II causes myocyte hypertrophy8 9 and fibroblast proliferation.9 Cultured neonatal rat cardiac myocytes synthesize and release Ang II, which is involved in mechanical stretch-induced hypertrophy of myocytes, thereby suggesting the important role of autocrine release of Ang II in cardiac hypertrophy.10 However, it is unknown whether the above-mentioned actions of Ang II in vitro can apply to the actions of Ang II in vivo.11

Pathological cardiac hypertrophy, induced by hypertension or pressure overload by aortic coarctation, is accompanied not only by quantitative changes (increase in cardiac myocyte size) but also by qualitative changes, including a shift to the fetal phenotype of myocytes5 12 13 14 15 and cardiac remodeling such as interstitial fibrosis.16 17 These qualitative changes in cardiac hypertrophy appear to participate in the modulation of cardiac systolic and diastolic functions.17 18 19 However, the mechanism of these qualitative changes remains to be determined. In the present study, to examine whether Ang II induces these qualitative changes of the heart, we continuously infused a low dose of Ang II into rats. We obtained direct evidence that Ang II, via the type 1 (AT1) receptor, can induce the shift to the fetal phenotype of cardiac myocytes and cardiac remodeling independent of hypertension.


*    Methods
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 up arrowIntroduction
 *Methods
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Drugs
Synthetic Ang II was purchased from Peptide Institute Inc. TCV-116,20 a nonpeptide selective AT1 receptor antagonist, was a gift from Takeda Chemical Industries, Ltd. Hydralazine, a vasodilator, was purchased from Wako Pure Chemical Industries, Ltd.

Continuous Ang II Infusion In Vivo
All procedures were in accordance with institutional guidelines for animal research. Experiments were performed on 8-week-old male Wistar rats (Clea Japan, Tokyo). They were fed a standard laboratory chow (CE-2, Clea Japan) and given tap water ad libitum. Rats were separated into four groups: (1) saline-infused group (control group), (2) Ang II–infused group, (3) Ang II–infused and TCV-116–treated (3 mg/kg per day) group, and (4) Ang II–infused and hydralazine-treated (10 mg/kg per day) group. For all four groups, rats were anesthetized with ether, and an Alzet osmotic minipump (model 1003D or 2001, Alza Corp) containing Ang II dissolved in saline or saline alone (control group) was implanted subcutaneously. Ang II was continuously infused into rats at 200 ng/kg per minute for 24 hours, 3 days, or 7 days. A previous study showed that long-term infusion of this Ang II dose causes a small and gradual increase in blood pressure.21 TCV-116 (3 mg/kg per day), suspended with 5% gum arabic solution, was given to rats orally by gastric gavage once a day from 1 day before implantation of the osmotic minipump to the end of Ang II infusion. Hydralazine (10 mg/kg per day), dissolved in the drinking water, was given to rats orally from 24 hours before the start to the end of Ang II infusion. At the indicated times, rats in each group were decapitated, and the heart was immediately excised. The left ventricle was carefully separated from the atria and right ventricle, weighed, immediately frozen in liquid nitrogen, and stored at -80°C until extraction of total RNA.

It is possible that Ang II infusion may change tissue water content by affecting electrolyte and volume balance. Therefore, in separate experiments, we measured the dry weight of the rat left ventricle after Ang II infusion. Rats, separated into the above-mentioned four groups, were decapitated at 24 hours, 3 days, or 7 days after the start of Ang II infusion, and the left ventricle was separated as described above and measured for wet weight. The left ventricular dry weight was determined after the tissue had been dried in an oven at 50°C for 5 days.

Oligonucleotide and cDNA Probes and Radiolabeling of Probes
Although there is a high degree of homology between the coding regions of rat {alpha}-myosin heavy chain (MHC) and ß-MHC mRNAs and among those of rat skeletal, cardiac, and smooth muscle {alpha}-actin mRNAs, the 3' untranslated regions are not closely conserved between the two MHC mRNAs22 23 and among the three {alpha}-actin mRNAs.24 25 26 Therefore, in the present study, to specifically detect each mRNA by Northern blot analysis, we used synthetic oligonucleotide probes complementary to the unique 3' untranslated regions of the two MHC mRNAs and three {alpha}-actin mRNAs. The sequences of oligonucleotide probes used were as follows: {alpha}-MHC, 5'-TTGTGGGATAGCAACAGCGA-3'23 ; ß-MHC, 5'-GTCTCAGGGCTTCACAGG-3'23 ; skeletal {alpha}-actin, 5'-GCAACCATAGCACGATGGTC-3'24 ; cardiac {alpha}-actin, 5'-TGCACGTGTGTAAACAAACT-3'25 ; and smooth muscle {alpha}-actin, 5'-CACAAAACATTCACAGTTGTGT-3'.26 The oligonucleotide probes were labeled with [{gamma}-32P]ATP (6000 Ci/mmol) at the 5' end using T4 polynucleotide kinase, and the labeled probes were purified by chromatography on a Bio-Spin 6 column (Bio-Rad).

The cDNA probes used were as follows: rat transforming growth factor-ß1 (TGF-ß1) cDNA, a HindIII–Xba I fragment27 ; rat fibronectin cDNA, a 0.27-kb HindIII-EcoRI fragment28 ; rat {alpha}1 (type I) collagen cDNA, a 1.3-kb Pst I–BamHI fragment29 ; mouse {alpha}1 (type III) collagen cDNA, a 1.8-kb EcoRI-EcoRI fragment30 ; rat atrial natriuretic polypeptide (ANP) cDNA, a 0.825-kb fragment, which was synthesized by reverse transcriptase–polymerase chain reaction followed by sequence analysis using the dideoxy method31 ; and rat glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a 1.3-kb Pst I–Pst I fragment.32 The cDNA probes were labeled with [32P]dCTP (specific activity, 3000 Ci/mmol; New England Nuclear) by random primer extension using a Random Primer DNA Labeling Kit (Takara).

RNA Extraction
Total RNA was isolated from the individual left ventricle by the guanidinium thiocyanate–phenol–chloroform method, as described.33 The RNA concentration was determined spectrophotometrically by absorbance at 260 nm.

Northern Blot Hybridization
Twenty micrograms of total RNA from the left ventricle was denatured in 1 mol/L glyoxal and 50% dimethyl sulfoxide at 50°C for 1 hour, separated on a 1% agarose gel, and transferred to a nylon membrane (GeneScreen Plus, DuPont Co), as described.33 The 28S and 18S ribosomal RNAs in gels were stained with ethidium bromide to demonstrate the integrity of applied RNA and to verify that the same amounts of RNA were applied to each lane. For hybridization with oligonucleotide probes, the membranes were prehybridized in a solution containing 20 mmol/L NaH2PO4 (pH 7.4), 6x SSC (1x SSC=0.15 mol/L sodium chloride, 0.015 mol/L sodium citrate, pH 7), 5x Denhardt's solution (1 mg/mL each of Ficoll, polyvinylpyrrolidone, and bovine serum albumin), 0.1% sodium dodecyl sulfate (SDS), and 200 µg/mL denatured salmon sperm DNA at 42°C for 4 hours and then hybridized in the same solution as prehybridization solution, containing the radiolabeled oligonucleotide probes, at 42°C for 24 hours. After hybridization, the membranes were washed in 2x SSC for 10 minutes at room temperature. Then the membranes were further washed in 2x SSC containing 1% SDS for 60 minutes. The washing temperatures were different among the oligonucleotide probes used: 55°C for {alpha}-MHC, 53°C for ß-MHC, 57°C for skeletal {alpha}-actin, 51°C for cardiac {alpha}-actin, and 55°C for smooth muscle {alpha}-actin. Finally, for all hybridizations to oligonucleotide probes, the membranes were washed in 0.1x SSC at room temperature for 20 minutes. For hybridization with cDNA probes, the conditions of prehybridization, hybridization, and membrane washing have been previously described.33

After washing, the membranes were exposed to x-ray films (X-Omat AR5, Eastman Kodak Co) between two intensifying screens at -70°C. The density of mRNA bands obtained by autoradiography was measured with a Macintosh LC-III computer with an optical scanner (Epson GT-8000, Seoko) and the public domain National Institutes of Health IMAGE program.33 The hybridization signals of specific mRNAs were divided by those of GAPDH mRNA to correct for differences in RNA loading and/or transfer. After autoradiography, the membranes were boiled in 0.1x SSC containing 1% SDS for 30 minutes to strip off the hybridized oligonucleotide or cDNA probe and were then rehybridized with another oligonucleotide or cDNA probe.

Blood Pressure Measurement
Systolic blood pressure of conscious rats infused with Ang II for 1, 3, or 6 days was measured by the tail-cuff method with a sphygmomanometer (Riken Development Co, Ltd). Each value is the average of three consistent readings.

Statistics
Results are expressed as mean±SEM. Data on body weight, blood pressure, left ventricular weight, and ventricular mRNA levels were analyzed by two-way ANOVA, and the differences between groups were determined by the least-square means test (SUPERANOVA, Abacus Concepts). Differences were considered statistically significant at a value of P<.05.


*    Results
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 *Results
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Effect of Ang II Infusion on Body Weight, Blood Pressure, and Left Ventricular Weight
Body weights of control, Ang II–infused, Ang II–infused and TCV-116–treated, and Ang II–infused and hydralazine-treated groups were 229±1, 229±2, 232±2, and 223±2 g (each n=10), respectively, at 24 hours; 234±2, 228±3, 234±1, and 228±4 g (each n=10), respectively, at 3 days; and 251±1, 249±7, 249±2, and 243±7 g (each n=4), respectively, at 7 days. Body weight was not significantly different among the four rat groups 24 hours, 3 days, or 7 days after Ang II infusion.

As shown in Fig 1A, blood pressure of Ang II–infused rats, indirectly measured by the tail-cuff method, tended to increase at 24 hours (129±2 versus 124±2 mm Hg in control) and increased significantly compared with control at 3 days (136±4 versus 127±2 mm Hg, P<.05) and 6 days (166±4 versus 125±2 mm Hg, P<.01). The blood pressure elevation by Ang II at 3 and 6 days was completely inhibited by treatment with TCV-116 or hydralazine.



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  		Figure 1. Bar graphs show effects of angiotensin II (Ang II) infusion (200 ng/kg per minute) on blood pressure and left ventricular wet weight. The ordinate in B indicates left ventricular wet weight corrected for body weight. Each bar represents mean±SEM. Each group consisted of 10 rats for 24 hours or 3 days of Ang II infusion and 4 rats for 7 days of infusion. TCV indicates TCV-116; Hyd, hydralazine.

As shown in Fig 1B, cardiac left ventricular wet weight did not increase at 24 hours after the start of Ang II infusion but increased significantly at 3 or 7 days. TCV-116 completely blocked the Ang II–induced increase in left ventricular wet weight, whereas hydralazine did not despite blood pressure normalization. It is possible that the increase in left ventricular wet weight by Ang II may be due to the increased tissue water content, because Ang II possibly accelerates the retention of sodium and body fluid. To exclude this possibility, in separate experiments we determined the dry weight of the left ventricle of Ang II–infused rats. As shown in Table 1, left ventricular dry weight was not increased by Ang II at 24 hours but was increased significantly at 3 or 7 days. These increases in dry weight by Ang II were completely inhibited by TCV-116 but not by hydralazine. Furthermore, there was no difference in the percentage of dry to wet weights of the left ventricle among the four groups, except for the slight decrease at 7 days of Ang II–infused rats. Thus, the results on dry weight were in good agreement with those on wet weight, thereby indicating that the increased left ventricular wet weight by Ang II was not due to increased tissue water content but to left ventricular hypertrophy.


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  		Table 1. Left Ventricular Dry Weight and Percentage of Dry to Wet Weights at 24 Hours and 3 and 7 Days After Start of Ang II Infusion

Effect of Ang II Infusion on Left Ventricular mRNAs for Five Contractile Proteins and ANP
As shown in Figs 2 and 3, skeletal {alpha}-actin, ß-MHC, and ANP mRNAs in the left ventricle were already increased by 6.9-, 1.8-, and 4.8-fold, respectively, at 24 hours after Ang II infusion; increased by 6.9-, 3.3-, and 7.5-fold, respectively, at 3 days; and remained elevated at 7 days. TCV-116 treatment completely blocked these increases in skeletal {alpha}-actin, ß-MHC, and ANP mRNAs at all time points examined. On the other hand, hydralazine did not at all suppress the increases in skeletal {alpha}-actin mRNA over 7 days, in ß-MHC mRNA at 24 hours, and in ANP mRNA at 24 hours. The increases in ß-MHC mRNA at 3 days and in ANP mRNA at 3 and 7 days were only partially inhibited by hydralazine. In contrast to the dramatic elevation of skeletal {alpha}-actin and ß-MHC mRNAs, cardiac {alpha}-actin mRNA increased only to a small extent (1.2-fold) only at 24 hours, and this increase was blocked by TCV-116 but not by hydralazine. Furthermore, left ventricular {alpha}-MHC and smooth muscle {alpha}-actin mRNA did not increase significantly throughout Ang II infusion. Therefore, as shown in Table 2, the ratios of skeletal {alpha}-actin to cardiac {alpha}-actin mRNAs and of ß-MHC to {alpha}-MHC mRNAs in the left ventricle were significantly increased at 24 hours and 3 days after the start of Ang II infusion, and this increase was completely prevented by TCV-116 but not by hydralazine. Thus, Ang II infusion dedifferentiated ventricular myocytes from an adult to a fetal phenotype.



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  		Figure 2. Typical autoradiograms of Northern blot analysis of left ventricular mRNAs for skeletal {alpha}-actin, cardiac {alpha}-actin, {alpha}-myosin heavy chain ({alpha}-MHC), ß-MHC, vascular smooth muscle {alpha}-actin ({alpha}-SMA), atrial natriuretic polypeptide (ANP), and GAPDH at 24 hours and 3 and 7 days after start of angiotensin II infusion. Lane 1, saline-infused group (control group); lane 2, angiotensin II–infused group; lane 3, angiotensin II–infused and TCV-116–treated group; lane 4, angiotensin II–infused and hydralazine-treated group. The sizes of mRNA bands were 1.7 kb for skeletal {alpha}-actin, 1.7 kb for cardiac {alpha}-actin, 7.1 kb for {alpha}-MHC, 7.1 kb for ß-MHC, 1.6 kb for {alpha}-SMA, 0.9 kb for ANP, and 1.4 kb for GAPDH.



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  		Figure 3. Bar graphs show left ventricular mRNA levels for five contractile proteins and atrial natriuretic polypeptide (ANP) at 24 hours and 3 and 7 days after start of angiotensin II (Ang II) infusion. In individual left ventricular RNA samples, each mRNA value was corrected for GAPDH mRNA value. The control group value at each time point is represented as 1. Each bar represents mean±SEM. Each group consisted of eight rats for 24 hours or 3 days of Ang II infusion and four rats for 7 days of infusion. TCV indicates TCV-116; Hyd, hydralazine; MHC, myosin heavy chain; and {alpha}-SMA, vascular smooth muscle {alpha}-actin. {dagger}P<.05, *P<.01 vs control; #P<.01 vs Ang II–infused group.


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  		Table 2. Ratios of Skeletal to Cardiac {alpha}-Actin mRNAs and ß-MHC to {alpha}-MHC mRNAs in the Left Ventricle at 24 Hours and 3 and 7 Days After Ang II Infusion In Vivo

Effect of Ang II Infusion on Left Ventricular TGF-ß1, Fibronectin, and Types I and III Collagen mRNA Levels
As shown in Figs 4 and 5, left ventricular TGF-ß1 mRNA levels were not elevated at 24 hours but increased by 1.4-fold (P<.01) at 3 days and remained elevated at 7 days. Fibronectin mRNA levels were already increased by 1.5-fold (P<.01) at 24 hours, reached a peak (2.5-fold) (P<.01) at 3 days, and returned to almost control levels at 7 days. Types I and III collagen mRNAs were not increased at 24 hours but began to increase by 2.8-fold (P<.01) and 2.1-fold (P<.01), respectively, at 3 days and remained elevated by 2.5-fold and 2.6-fold, respectively, at 7 days. TCV-116 treatment completely blocked all the above-mentioned Ang II–induced increases in TGF-ß1, fibronectin, and types I and III collagen mRNAs, whereas treatment with hydralazine could not inhibit these increases in mRNAs by Ang II, except for partial suppression of types I and III collagen mRNA expression at 3 days.



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  		Figure 4. Typical autoradiograms of Northern blot analysis of left ventricular mRNAs for transforming growth factor-ß1 (TGF-ß1), fibronectin, collagen type I, collagen type III, and GAPDH at 24 hours and 3 and 7 days after start of angiotensin II infusion. Lane 1, saline-infused group (control group); lane 2, angiotensin II–infused group; lane 3, angiotensin II–infused and TCV-116–treated group; lane 4, angiotensin II–infused and hydralazine-treated group. The sizes of mRNA were 2.5 kb for TGF-ß1, 7.9 kb for fibronectin, 4.7 and 5.7 kb for collagen I, 5.9 kb for collagen III, and 1.4 kb for GAPDH.



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  		Figure 5. Bar graphs show left ventricular mRNA levels for transforming growth factor-ß1 (TGF-ß1), fibronectin, type I collagen, and type III collagen at 24 hours and 3 and 7 days after start of angiotensin II (Ang II) infusion. In individual left ventricular RNA samples, each mRNA value was corrected for GAPDH mRNA value. Each bar represents mean±SEM. The control group value at each time point is represented as 1. Each group consisted of eight rats for 24 hours or 3 days of Ang II infusion and four rats for 7 days of infusion. TCV indicates TCV-116; Hyd, hydralazine. {dagger}P<.05, *P<.01 vs control; #P<.01 vs Ang II–infused group.


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
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Accumulating evidence supports the notion that the renin-angiotensin system exists not only in the blood circulation but also in cardiac tissues.34 35 Recently, it has been reported that Ang II induces hypertrophy of cultured cardiac myocytes from neonatal rats9 and embryonic chick8 and also causes the proliferation of cultured neonatal rat cardiac fibroblasts.9 Furthermore, very recently, using an in vitro model of load (stretch)-induced cardiac hypertrophy, Sadoshima et al10 have obtained evidence showing that mechanical stretch leads to release of Ang II from neonatal rat ventricular myocytes and the released Ang II acts as an initial mediator of the stretch-induced hypertrophic response. All these findings, obtained by in vitro studies,8 9 10 support the notion that autocrine release of Ang II from cardiac myocytes is involved in load (stretch)-induced growth of ventricular myocytes, thereby suggesting the central role of Ang II in cardiac hypertrophy and remodeling. However, it remains to be determined whether the actions of Ang II in vitro apply to those in vivo. It is also still unknown whether Ang II, independent of blood pressure, contributes to the pathophysiology of cardiac hypertrophy and remodeling in vivo. Furthermore, there is a significant difference in the mechanism of hypertrophy between neonatal and adult cardiac myocytes.11 Thus, in vivo study is essential to define the true role of Ang II in the pathophysiology of cardiac hypertrophy and remodeling. These findings led us to investigate the effect of Ang II on cardiac gene expression in vivo.

In the present study, blood pressure, indirectly measured by the tail-cuff method, tended to be increased at 24 hours after Ang II infusion at 200 ng/kg per minute, although not statistically significant, which was consistent with a previous report.21 However, no significant blood pressure elevation after 24 hours of Ang II infusion might be due to the lack of sensitivity of the tail-cuff method. Therefore, in separate experiments, we measured the arterial blood pressure of Ang II–infused (200 ng/kg per minute) conscious rats directly via the femoral artery and found that this Ang II dose significantly increased mean arterial blood pressure by 9 mm Hg after 24 hours (data not shown), thereby indicating that no blood pressure elevation at 24 hours in the present study was due to the lack of sensitivity of the tail-cuff method. Thus, this dose of Ang II used in the present study caused a small and gradual increase in blood pressure over 7 days.

Left ventricular weight was not increased by Ang II at 24 hours but significantly increased at 3 and 7 days. Cardiac hypertrophy by Ang II was completely blocked by an AT1 receptor antagonist. On the other hand, treatment with hydralazine, which completely normalized blood pressure, did not suppress cardiac hypertrophy by Ang II at 3 or 7 days, findings similar to those in a report by Dostal and Baker.36 These observations suggest that the AT1 receptor may be directly involved in cardiac growth in vivo.

Pathological cardiac hypertrophy is characterized not only by an increase in myocyte size but also by reexpression of fetal isoforms of contractile proteins such as ß-MHC and skeletal {alpha}-actin.12 13 14 15 In the cardiac ventricle of most mammalian species, including humans, MHC consists of the {alpha} and ß isoforms.18 In the rat, {alpha}-MHC is the predominant isoform of adult hearts, and ß-MHC is the predominant isoform of fetal hearts. Cardiac sarcomeric actin is also composed of two isoforms, cardiac and skeletal {alpha}-actins.18 Cardiac {alpha}-actin is predominantly expressed in adult rat hearts, and skeletal {alpha}-actin is normally expressed in fetal and neonatal rat hearts. In the rat model of pressure overload by aortic coarctation or stenosis, the expression of ß-MHC13 14 15 and skeletal {alpha}-actin12 15 is dramatically increased in the hypertrophic ventricle, which results in increased ratios of ß- to {alpha}-MHCs and of skeletal to cardiac {alpha}-actins in the hypertrophic ventricle. The ratio of ß-MHC to {alpha}-MHC in the ventricle is of physiological importance, because this ratio is closely correlated with the contractile properties of the heart.18 The {alpha}-MHC, which has high Ca2+ and actin-activated ATPase activity, is associated with an increased shortening velocity of the cardiac fibers. In contrast, the ß-MHC, which has lower ATPase activity, is associated with slower shortening velocity. The ratio of skeletal {alpha}-actin to cardiac {alpha}-actin is also physiologically important because skeletal {alpha}-actin causes a greater contractility than cardiac {alpha}-actin.19 Thus, the enhanced expression of fetal isoforms of contractile proteins (ß-MHC and skeletal {alpha}-actin) in the hypertrophic ventricle may play an important role in the modulation of cardiac performance. However, the regulating mechanism of gene expression of these fetal isoforms in vivo remains to be determined. Interestingly, the enhanced expression of the fetal isoforms is not an obligatory process for myocardial growth, because in vivo administration of thyroid hormone to rats causes ventricular hypertrophy but significantly decreases ventricular ß-MHC (fetal isoform) expression and increases {alpha}-MHC (adult isoform) expression.13 14 23 Of note are the observations that the gene expression of two fetal isoforms of contractile proteins, ß-MHC and skeletal {alpha}-actin, in the left ventricle was already significantly increased at 24 hours after Ang II infusion, preceding the increase in left ventricular weight. Thus, Ang II induces the shift to the fetal phenotype of cardiac myocytes in a more sensitive manner than it induces significant myocyte growth. On the other hand, the gene expression of ventricular {alpha}-MHC was not changed, and cardiac {alpha}-actin was enhanced only to a slight extent only at 24 hours. In addition, there was no alteration of ventricular mRNA for vascular smooth muscle {alpha}-actin, which is abundantly expressed in the contractile phenotype of vascular smooth muscle cells. These observations provide evidence that Ang II selectively stimulates the gene expression of fetal isoforms of contractile proteins in ventricular myocytes, thereby suggesting that Ang II in vivo may be an important direct regulator of cardiac performance. Furthermore, as rapidly and potently as the fetal isoforms of contractile proteins, Ang II also stimulated the gene expression of ventricular ANP, which is a useful marker of the fetal phenotype of ventricular myocytes and is well known to be dramatically induced in the hypertrophic myocardium by hemodynamic overload.14 Thus, the pattern of reprogramming of ventricular gene expression by Ang II is similar to that by hemodynamic overload,12 13 14 15 and it differs significantly from that by thyroid hormone, which causes cardiac hypertrophy without the induction of fetal contractile protein and ANP expressions.13 14 23 Furthermore, the cardiac phenotypic modulation by Ang II was not prevented by blood pressure normalization with hydralazine treatment, thereby supporting the hypothesis that Ang II may be directly responsible for the cardiac phenotypic modulation.

Pathological cardiac hypertrophy is associated with not only the phenotypic modulation of myocardium but also cardiac remodeling, which is characterized by increased deposition of extracellular matrix such as collagen and fibronectin in the interstitium and perivascular fibrosis.16 17 37 The increased interstitial collagen (mainly composed of types I and III collagen) in the heart enhances organ stiffness and results in diastolic dysfunction, which finally leads to heart failure.17 Fibronectin is localized along the surface of cardiac myocytes, connects cardiac myocytes to perimyocytic collagen, and is therefore suggested to affect cardiac systolic and diastolic functions.38 Thus, the increased deposition of extracellular matrix proteins in the interstitium significantly affects cardiac performance. In pressure-overloaded rat myocardium, the increase in ventricular types I and III collagen mRNAs occurs at 3 days after pressure overload, and fibronectin mRNA begins to increase at 24 hours.37 In the present study, we found significant stimulation of ventricular types I and III collagen and fibronectin mRNAs by exogenously administered Ang II, which was not prevented by blood pressure normalization with hydralazine treatment. Therefore, it is suggested that Ang II in vivo may directly contribute to cardiac remodeling. Interestingly, the increase in fibronectin mRNA by Ang II occurred at 24 hours, whereas the increase in collagen mRNAs occurred later (at 3 days), thereby indicating that the effects of Ang II on fibronectin and types I and III collagen expression mimicked those by pressure overload.37 Furthermore, very recently, Crawford et al39 reported that infusion of a high dose of Ang II into rats, elevating systolic blood pressure to 170 mm Hg at 24 hours after the infusion, increases ventricular fibronectin mRNA at 24 hours and type I collagen mRNA at 3 days, thereby indicating the similarity between the low and high doses of Ang II with respect to the effects on extracellular matrix gene expressions. Thus, mechanisms of the increase in mRNA by Ang II may differ between ventricular fibronectin and collagen. The increase in collagen mRNA by Ang II may be secondary to the proliferation of cardiac fibroblasts.40

TGF-ß1, a multifunctional growth factor, regulates cell growth and stimulates the production of collagen and fibronectin, thereby possibly contributing to cardiac myocyte growth and remodeling.41 42 43 It has been reported that TGF-ß1 in vitro provokes the gene expression of fetal contractile proteins (ß-MHC and skeletal {alpha}-actin) in neonatal rat cardiac myocytes.44 Furthermore, increased TGF-ß1 mRNA has been found in the hypertrophic ventricle by pressure overload.7 37 These findings, taken together with the fact that Ang II stimulates TGF-ß1 gene expression in cultured cells,45 suggest that the increased cardiac mass and increased gene expression of fibronectin, collagen, and fetal contractile proteins by Ang II may be mediated by TGF-ß1. To determine this possibility, in the present study we measured ventricular TGF-ß1 mRNA levels. Our present study provides evidence that Ang II increases ventricular TGF-ß1 mRNA independent of hypertension. However, the increased TGF-ß1 mRNA occurred at 3 days after Ang II infusion, thereby suggesting that the increased cardiac weight at 7 days may be partially due to the increased TGF-ß1, whereas the increased fibronectin, collagen, and fetal contractile protein mRNAs by Ang II seem not to be mediated by TGF-ß1.

In the present study, treatment with TCV-116, a selective nonpeptide AT1 receptor antagonist, completely inhibited the Ang II–induced increases in cardiac weight and fetal contractile protein, fibronectin, types I and III collagen, and TGF-ß1 mRNAs. Thus, the AT1 receptor seems to play a central role not only in hypertension but also in phenotypic modulation and cardiac remodeling. Therefore, it is possible that an AT1 receptor antagonist may be a powerful therapeutic agent for cardiac hypertrophy and heart failure.

In conclusion, Ang II in vivo, via the AT1 receptor, causes not only ventricular hypertrophy but also a shift to the fetal phenotype of myocardium and stimulation of extracellular matrix and TGF-ß1 expressions, which may play an important role in the modulation of cardiac performance. These effects by exogenously infused Ang II mimic those by pressure overload.12 13 14 15 16 17 37 Therefore, the present results, taken together with in vitro evidence that mechanical stretch-induced hypertrophy of cardiac myocytes is mediated by autocrine release of Ang II from cardiac myocytes,10 suggest that the shift to the fetal phenotype of cardiac myocytes and cardiac remodeling, induced by hemodynamic overload such as hypertension and aortic stenosis, may be due to the autocrine release of Ang II. However, further study is needed to elucidate our proposal.


*    Acknowledgments
 
This work was supported in part by a Grant-in-Aid for Scientific Research (05770067 and 05670100) from the Ministry of Education, Science, and Culture; by a grant provided by the Ichiro Kanehara Foundation; and by the Osaka City University Medical Research Foundation Fund for Medical Research. We are grateful to Eriko Gomi for her technical assistance.


*    Footnotes
 
Reprint requests to Shokei Kim, MD, Department of Pharmacology, Osaka City University Medical School, 1-4-54 Asahimachi, Abeno, Osaka 545, Japan.

Received January 6, 1995; first decision January 27, 1995; accepted January 27, 1995.


*    References
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 up arrowDiscussion
 *References
 

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