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(Circulation. 1995;92:1223-1229.)
© 1995 American Heart Association, Inc.

Articles

Acute Hypertension Induces Heat-Shock Protein 70 Gene Expression in Rat Aorta

Qingbo Xu, MD; Ding-gang Li, MD; Nikki J. Holbrook, PhD; Robert Udelsman, MD

Correspondence to Dr Qingbo Xu, Section on Gene Expression and Aging, National Institute on Aging, National Institutes of Health, 4940 Eastern Ave, Baltimore, MD 21224.

	Abstract

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Background Many factors cause acute systemic hypertension, which in turn can result in damage to the vessel wall and lead to vascular disease. In previous studies, we demonstrated that restraint, or immobilization stress, results in the induction of heat-shock protein 70 (hsp70) gene expression in the aorta of adult rat and showed that this response was markedly attenuated with age.

Methods and Results Here we provide evidence that restraint-induced hsp70 expression occurs secondary to a rise in systemic blood pressure. Old rats were unable to mount a significant stress-induced hypertensive response, providing an explanation for the reduced hsp70 response in the old rats. A variety of vasoactive agents that induce acute hypertension through distinct signal transduction pathways, including phenylephrine, dopamine, vasopressin, angiotensin II, and endothelin-1, were found to result in hsp70 mRNA induction in the aorta. The magnitude of hsp70 expression achieved with these hypertensive agents was directly correlated with their relative effects on blood pressure. Rats were treated with the vasodilator sodium nitroprusside, which prevented an acute rise in blood pressure from the hypertensive agents tested and abolished induction of hsp70 expression.

Conclusions These findings support the conclusion that hsp70 induction occurs as a physiological response to acute hypertension and suggest the possibility that hsp70 plays a role in the protecting the vasculature from damage during hemodynamic stress.

Key Words: hypertension • proteins, heat shock • aorta • stress

	Introduction

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Heat-shock proteins (hsps) are a set of related proteins that are induced by a variety of stresses, including heat, toxic substances, injury, surgery, and even behavioral or psychological stresses.^{1 2} The ubiquitous nature of the so-called heat-shock response and its phylogenetic conservation suggest that hsps are essential for cell survival.³ Although the specific functions of the various members of the hsp family remain to be elucidated, there is evidence that several hsps interact with other cellular proteins to assist in their assembly, disassembly, stabilization, and transport.^{4 5}

Most of our knowledge concerning the regulation and function of hsps has come from studies of cultured cells.^{6 7 8} Much less is known about their expression in vivo, although it is clear that hsps are induced in the intact animal in response to a variety of stresses.^{9 10 11} Recently we reported^{12 13 14} that restraint (immobilization stress) and surgical stress resulted in the selective induction of hsp70 mRNA and protein in the adrenal cortex and vasculature of rats. Both tissue responses have been characterized in detail and have been shown to decline with age. With respect to the vascular response, we showed that hsp70 induction is confined to the smooth muscle cell layer of the vessel.^{13 14} Restraint-induced expression in the aorta could be blocked by administration of the ₁-adrenergic antagonist prazosin and induced by treatment with the ₁-adrenergic agonist phenylephrine, suggesting that the vascular hsp70 induction in restrained rats is mediated by means of ₁-adrenoceptors.¹³ Recent studies by others have indicated that the vascular response to restraint can also be mimicked, at least to some extent, by dopamine and cocaine.^{15 16} These agents exert their effects through interaction with receptors distinct from the ₁-adrenoceptor. Such findings raise the question of whether the activation of ₁-adrenoceptors on smooth muscle cells during restraint directly leads to activation of the heat-shock response or whether the hsp expression occurs secondary to some other receptor-mediated event. Since phenylephrine, dopamine, and cocaine all can elevate blood pressure, we examined the relation between blood pressure and vascular hsp70 expression. We demonstrate here that acute hypertension leads to the induction of hsp70 in rat aorta, and we provide evidence that this is the mechanism through which restraint elicits this stress response. In addition, we provide evidence that the age-related attenuation in vascular hsp70 expression primarily is due to a reduction or absence of the hypertensive response to restraint.

	Methods

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Rats and Restraint Model
Male Fischer 344 rats, 6 months old (young adult rats) and 24 months old (old rats), were obtained from the rat colony maintained by Charles River Breeding Laboratory (Wilmington, Mass) for the National Institute on Aging. Spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) control rats were purchased from Taconic Farms, Inc (Germantown, NY). All rats were acclimated in individual cages for one week before experimentation. They were maintained on a 12-hour light/dark cycle at 24°C and received food and water ad libitum. All procedures were performed according to protocols approved by the institutional committees responsible for the care and use of laboratory rats in accordance with guidelines established by the National Institutes of Health. For restraint experiments, rats were placed in a clear ventilated Plexiglas chamber for a 60-minute period, as described previously.¹³

Blood Pressure Measurements
Rats underwent light anesthesia with thiopental (40 mg/kg IM) followed by insertion of polyethylene catheters through the common femoral artery and vein into the abdominal aorta and inferior vena cava, respectively.¹³ The aortic catheter was connected to a pressure transducer (COBE) and a blood pressure analyzer (Micro-MED, Inc). A bolus injection of various reagents or saline was administered through the vena caval catheter, and blood pressure measurements were made every 30 seconds for 10 or 60 minutes. The doses of the pharmacological agents were calculated on a microgram per kilogram basis as determined by their ability to produce consistent hypertensive responses without demonstrable side effects.

Chronic Catheterization Procedure and Drug Administration
Polyethylene catheters were inserted through the common femoral vein into the inferior vena cava under thiopental (40 mg/kg IM) anesthesia.¹³ The catheters were tunneled through the subcutaneous tissue to exit from the back, where they were connected to a swivel device (Rodent Multi-fluid Channel Swivel, Stoelting Co). This model allows for complete rat mobility so that subsequent experiments could be performed in conscious, unstressed rats. Saline (0.4 mL) was injected through the catheter daily for 4 days after catheter insertion. Phenylephrine (140 µg/kg), dopamine (250 µg/kg), vasopressin (2 µg/kg), angiotensin II (Ang II) (2 µg/kg), and endothelin-1 (1 µg/kg) (Sigma Chemical Co) were administered through the catheter into the vena cava. For blocking experiments, sodium nitroprusside (600 µg/kg) (Sigma) was injected, followed immediately by the hypertensive agents at the doses described above. One hour after reagent or saline administration, the rats were euthanatized and tissues were harvested for RNA preparation.

Cell Culture
Smooth muscle cells were isolated by enzymatic digestion of the aorta from rats according to the procedure of Ross and Kariya¹⁷ and cultured in medium 199 (GIBCO) supplemented with 20% fetal calf serum, penicillin (100 U/mL), and streptomycin (100 µg/mL). Cells were incubated at 37°C in a humidified atmosphere of 95% air/5% CO₂. The medium was changed every 3 days, and cells were passaged by treatment with 0.05% trypsin/0.02% EDTA solution. Experiments were conducted on smooth muscle cells (passages 3 through 5) that had just achieved confluence. Rat serum or various drugs prepared fresh before use were added to the cultures. After incubation for 1 hour at 37°C, cells were harvested for RNA analysis.

RNA Extraction and Northern Analysis
Freshly harvested tissues were homogenized, and the RNA was extracted by use of RNAzol B (Cinnabiotex). Total RNA (10 µg per lane) was fractionated by electrophoresis on formaldehyde-agarose gels and transferred to nylon membranes (Gene Screen Plus, Du Pont Co). Hybridizations were performed using -³²P–labeled cDNA hsp70 probe, as previously described.¹² Accuracy of loading and transfer was confirmed by quantitative analysis of 18s and 28s RNA. Autoradiographs of the blots were obtained in the linear range of detection and were quantified for the levels of specific expression by scanning laser densitometry (Molecular Dynamics) of autoradiographs.

Statistical Analysis
ANOVA was performed when more than two groups were compared. Paired Student's t test was used to assess differences between two groups after ANOVA. A value of P<.05 was considered significant.

	Results

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Acute Elevations in Blood Pressure Lead to HSP70 Induction
To determine a possible relation between blood pressure elevation and aortic hsp70 expression, arterial blood pressure was measured and aortic hsp70 mRNA was analyzed after either restraint stress or administration of specific vasoactive agents. As shown in Fig 1A, use of restraint resulted in a rapid rise (within 5 minutes) in systemic blood pressure (systolic, from 120 to between 150 and 160 mm Hg), which was maintained for the entire period of restraint (60 minutes). The effects of the various vasoactive pharmacological agents on blood pressure are shown in Fig 1B. Phenylephrine, dopamine, Ang II, and vasopressin all caused an acute elevation in systemic blood pressure. Although the maximum systolic pressure obtained with each of these agents was higher than that achieved with restraint, in all cases, the pressure returned to baseline within 10 minutes of injection (Fig 1B). At the dose used, endothelin-1 had a relatively lesser effect on blood pressure than the other agents. Although the blood pressure was elevated to 160 mm Hg (similar to restraint), the effect was short-lived, returning to baseline levels within 3 minutes of injection. Higher doses could not be used because of toxicity related to its direct effect on heart contractility. The effects of these treatments on hsp70 mRNA levels are shown in Fig 1C. Phenylephrine, dopamine, Ang II, and vasopressin all caused a significant induction of hsp70 mRNA. Consistent with its lesser effect on blood pressure, endothelin-1 treatment resulted in less induction of hsp70 mRNA. The ability of these agents to induce hsp70 expression was specific to the vasculature because other tissues, including heart, liver, spleen, lung, adrenal gland, and testis, did not show any increase in hsp70 mRNA levels (data not shown).

View larger version (35K): [in this window] [in a new window]   Figure 1. Effects of restraint and vasoconstrictor agents on blood pressure and aortic heat-shock protein 70 (hsp70) mRNA expression. A and B, Line graphs showing arterial systolic blood pressure of male Fischer 344 rats during 60 minutes of restraint vs nonrestraint (A; n=3 per group) and after a bolus injection of various drugs, including phenylephrine (140 µg/kg), dopamine (250 µg/kg), vasopressin (2 µg/kg), angiotensin II (2 µg/kg), and endothelin-1 (1 µg/kg), (B; n=3 per group). Values are means of systolic blood pressure from three rats per group. C, Northern blot analysis and bar graph of hsp70 expression in total RNA (10 µg per lane) of aorta harvested from individual rats after either 60 minutes of restraint or drug administration. Blots were hybridized sequentially with hsp70 and 18s probes. Data in C are mean±SD of three independent experiments (n=3 per group). *Significantly different from control, P<.05.

To further establish the relation between blood pressure and hsp70 expression, we performed a dose-response analysis of vasopressin-induced hypertension and aortic hsp70 mRNA induction. As in Fig 2, blood pressure levels and hsp70 mRNA expression increased in parallel as a function of the dose of vasopressin.

View larger version (34K): [in this window] [in a new window]   Figure 2. Line graph showing dose-dependent increase in systolic blood pressure and aortic hsp70 mRNA levels of hsp achieved with the indicated doses of vasopressin. Values are mean±SD of three independent experiments. Inset, Northern blot for one experiment examining heat-shock protein 70 (hsp70) mRNA. Aorta was harvested after 60 minutes of treatment. Lane 1, no treatment; lanes 2, 3, 4, 5, and 6, treatment with 0.25, 0.5, 1.0, 2.0, and 2.8 µg/kg vasopressin, respectively.

Kinetic analysis of the hsp70 responses to restraint and vasopressin treatment is shown in Fig 3. In the restraint protocol used for Fig 3A, rats were left in the restraint device for the entire length of time indicated on the x axis, at which time they were euthanatized and analyzed for hsp70 expression. In the experiment shown in Fig 3B, rats were restrained for the length of time indicated on the x axis (5, 10, 30, or 60 minutes) then removed and left unrestrained for the remainder of time: up to 60 minutes after they first were restrained. As can be seen, the response to both restraint and vasopressin was rapid, resulting in maximum mRNA levels within 30 minutes of vasopressin treatment or sustained restraint. As shown in Fig 3B, however, the magnitude of induction seen at 60 minutes was dependent on the length of time the rats were restrained (up to 30 minutes). Importantly, a short period of restraint (5 minutes) was insufficient to result in significant hsp70 induction. This is consistent with the inability of endothelin-1 (which transiently elevated blood pressure to the same degree as restraint) to induce hsp70 expression. Thus, for moderate elevations in blood pressure (such as those occurring with restraint or the dose of endothelin-1 used in the present study), a sustained elevation in blood pressure is necessary to achieve maximum hsp70 expression. With higher elevations of blood pressure (such as those occurring with vasopressin and the other hypertensive agents used), however, a lesser duration of hypertension is required.

View larger version (42K): [in this window] [in a new window]   Figure 3. Time course of restraint-induced and vasopressin-induced heat-shock protein 70 (hsp70) expression. A, Rats were euthanatized at the indicated time points after vasopressin administration or placement in the restraint device. B, Rats were restrained for the indicated time (x axis), then returned to their cages for the remainder of the time period (up to 60 minutes), at which time they were euthanatized and analyzed for hsp70 expression. Total RNA (10 µg) was extracted from rat aorta and assayed for hsp70 mRNA expression by Northern blot analysis. Values for each time point are mean±SD of expression obtained in four individual rats. *Significantly different from control (P<.05).

Antihypertensive Agents Can Block HSP70 Expression
The various agents tested above mediate their effects on blood pressure by interaction with distinct receptors on the surface of smooth muscle cells. It was of interest, therefore, to determine whether hsp70 expression induced by any of these agents could be prevented by use of a nonspecific vasodilatory agent. Accordingly, sodium nitroprusside was administered before injection of the hypertensive agents. As Fig 4A shows, sodium nitroprusside alone caused a pronounced decrease in systemic blood pressure. In addition, it prevented elevation in blood pressure by vasopressin (Fig 4A), phenylephrine, Ang II, dopamine, and endothelin-1 (Fig 4B). Measurement of hsp70 mRNA levels in similarly treated rats revealed that sodium nitroprusside uniformly prevented hsp70 induction in response to these treatments (Fig 4C).

View larger version (35K): [in this window] [in a new window]   Figure 4. Sodium nitroprusside (SN) (600 µg/kg) prevents elevations in blood pressure and abolishes aortic heat-shock protein 70 (hsp70) mRNA induction. A and B, Line graphs showing systolic pressure measurements achieved with the various treatments (n=3 per group). C, Representative Northern blot showing hsp70 mRNA expression obtained after treating rats with various vasoactive agents in the presence of SN.

These experiments indicate that induction of vascular hsp70 expression by restraint and the other agents tested depends on an elevation in blood pressure. Further support for this notion was obtained from studies examining the effects of these agents on hsp70 expression in primary aortic smooth muscle cell cultures. We reasoned that if hsp70 expression were mediated by means of receptor interactions independent of the effects of these agents on blood pressure, we would expect to observe induction in the in vitro model, at least by some of the agents. On the other hand, if induction occurred secondary to the blood pressure elevation these agents caused, hsp70 expression would not increase in cultured cells. As Fig 5 shows, no increase in hsp70 expression was observed in the smooth muscle cell cultures with any of the treatments, although hsp70 mRNA was strongly induced in these cells in response to heat treatment. The modest increase was observed in hsp70 mRNA levels in cultures treated with 20% rat serum (in addition to the 20% fetal bovine serum in which all cultures were maintained) because hsp70 expression has previously been shown to be elevated in response to serum. The purpose of this treatment was to determine whether serum from restrained rats contained a factor that was responsible for hsp70 induction. Because the levels of hsp70 mRNA were similar in cells treated with serum from unrestrained as well as restrained rats, this appears not to be the case. These findings, together with the ability of sodium nitroprusside to prevent induction, argue strongly that hsp70 induction occurs in response to elevated systemic blood pressure.

View larger version (66K): [in this window] [in a new window]   Figure 5. Northern blot analysis of heat-shock protein 70 (hsp70) expression in cultured smooth muscle cells treated with vasoactive agents. Smooth muscle cells were dissociated from rat aorta by collagenase and cultivated in medium 199. Confluent cells were incubated with various drugs at 37°C for 60 minutes. For heat-shock (42°), cells in normal medium were placed at 42°C for 30 minutes followed by an additional 30 minutes at 37°C. After incubation, total RNA was isolated and analyzed by Northern blot for hsp70 expression. Data are an example from similar results of three independent experiments. 18S indicates 18s RNA.

HSP70 Expression in Aorta of Rats Displaying Chronic Hypertension
In view of the effect of acute elevations in blood pressure on hsp70 expression, it was of interest to examine whether expression of the hsp was affected by chronic hypertension. To address this question, we examined blood pressure and hsp70 mRNA expression in SHR either left unrestrained or after being restrained for 1 hour. These rats exhibit normal blood pressure at birth but spontaneously develop chronic hypertension with increasing age.¹⁸ As shown in Fig 6A, under non-stress conditions, their systolic pressure averaged 160 mm Hg, which was similar to that seen in our Fischer 344 rats subjected to restraint. Restraint resulted in an elevation in blood pressure to 180 mm Hg. In Fig 6B, hsp70 mRNA levels are compared in SHR and WKY rats (the normotensive rat strain from which SHR were derived) under restraint and not restrained. No differences were observed in hsp70 expression in the SHR compared with WKY rats either in the absence of stress or after restraint. Thus, hsp70 expression appears to depend on acute changes in blood pressure regardless of the baseline blood pressure level seen in the absence of stress. These findings suggest that chronic hypertension results in an adaptation to elevated blood pressure and thus a resetting of the threshold for hsp70 induction.

View larger version (28K): [in this window] [in a new window]   Figure 6. Changes in blood pressure and heat-shock protein 70 (hsp70) expression in aorta of spontaneously hypertensive rats (SHR) subjected to restraint. A, Line graph showing arterial systolic pressure in 3-month-old male Wistar-Kyoto rats (Kyoto in figure, control) and SHR during 10 minutes of nonrestraint and 60 minutes of restraint (mean, four rats per group). B, Northern blot analysis of hsp70 expression in aorta of unrestrained and restrained rats. Results are mean±SD of hsp70 expression in four rats.

Correlation of Age-Related Decline in Restraint-Induced hsp70 Expression With Lack of Restraint-Induced Increases in Blood Pressure
We previously reported¹³ that the magnitude of hsp70 mRNA induction in response to restraint was significantly reduced in old rats compared with young adult rats. In view of the relation between blood pressure and aortic hsp70 expression established above, we compared the effect of restraint on blood pressure in young and old rats (Fig 7A). Young rats responded to restraint with an elevation in blood pressure, consistent with the findings presented in Fig 1. In contrast, blood pressure did not increase in old rats during restraint. Next, we determined whether old rats were able to respond to hypertension-inducing agents with the induction of hsp70 expression. The effects of optimal doses of phenylephrine and vasopressin on blood pressure and hsp70 expression were examined. At the dose tested, both agents had a lesser effect on blood pressure in old compared with young rats (Fig 7B). However, on the basis of the dose-response relation for elevated blood pressure and hsp70 expression established in Fig 2, the rise in blood pressure seen with phenylephrine and vasopressin is expected to be sufficient to induce hsp70 expression. This is indeed what we observed (Fig 7C).

View larger version (56K): [in this window] [in a new window]   Figure 7. Effects of restraint, phenylephrine, and vasopressin on blood pressure and aortic heat-shock protein 70 (hsp70) expression in old rats. A, Line graph and Northern blot (inset) comparing changes in systolic pressure in young adult (Y) (6 months old) and old (O) (24 months old) Fischer 344 rats in response to restraint (n=3 per group). Inset shows aortic hsp70 mRNA levels in representative young and old rats subjected to restraint. B, Line graph of changes in blood pressure in young and old rats after treatment with phenylephrine and vasopressin (n=3 per group). C, Northern blot showing aortic hsp70 mRNA levels in young and old rats treated with agents indicated.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Previously we reported that restraint of rats results in high levels of hsp70 expression in rat aorta, and by use of selective adrenoceptor agonists and antagonists, we provided evidence that the response could be mediated through ₁-adrenoceptors.¹³ In this article, we provide new findings that indicate that hsp70 induction in the aorta occurs not as a primary response to ₁-adrenergic hormone-receptor signal transduction but secondary to acute hypertension. This conclusion is based on five observations: (1) In addition to the ₁-adrenergic agonist phenylephrine, four additional agents that act through distinct receptors to elevate blood pressure all selectively induced expression of hsp70 mRNA in the rat aorta. (2) The dose-response relation for the induction of hsp70 mRNA by vasopressin and the efficacies of the other agents tested for inducing hsp70 were directly correlated with their relative effects on blood pressure. (3) The vasodilator sodium nitroprusside, which acts nonspecifically to prevent increases in blood pressure with each of the above agents, likewise blocked the induction of hsp70 expression by each. (4) Old rats, which show less induction of hsp70 in response to restraint, display little elevation in blood pressure after restraint. (5) This in vivo response is not observed in vitro when primary cultures of vascular smooth muscle cells are treated with these agents. Taken together, these findings support the hypothesis that induction of hsp70 expression in the aorta occurs as a physiological response to acute hypertension and suggest the possible involvement of hsp70 either in protecting the vessel from injury during hemodynamic stress or in maintaining vascular homeostasis.

In agreement with our findings, Moalic et al¹⁹ likewise showed that hsp70 mRNA expression was induced in rat aorta after injection with phenylephrine, vasopressin, or Ang II. However, they proposed that the hsp induction occurred as a primary response to the interaction of ligands with specific receptors on the aorta rather than to changes in arterial blood pressure. While we cannot exclude the possibility that direct effects of these agents on the aorta contribute to the response, for the reasons summarized above, they are unlikely to be the main determinant of aortic hsp70 expression in response to the hypertensive agents.

All the agents used in our study increase systemic blood pressure primarily through constriction of peripheral arterioles. This in turn results in stretching of the large arterial wall. While the mechanism of aortic hsp70 mRNA induction remains to be elucidated, we postulate that the induction during acute hypertension may be due to mechanical stress resulting from hemodynamic alterations. This mechanism is consistent with our earlier observation that the response is not restricted to the major arterial vessels but also occurs in the vena cava.¹³ In addition, it was shown that a single myocardial stretch could induce hsp70 expression in isolated perfused rabbit heart²⁰ and volume overload produced experimentally by banding of the aorta was sufficient to elicit hsp70 induction in the heart.²¹ However, an in vitro study showed a lack of stretch-induced expression of hsp70 gene in cultured cardiac myocytes,²² suggesting that other factors or subsequent events may be needed for hsp70 induction in the process of cell stretching.

A general feature of the heat-shock response in cultured cells is that it undergoes an attenuation during prolonged treatment with a given stress inducer, which in certain instances is believed to reflect an adaptive response to the stress.^{23 24} Chronic hypertension may represent a similar situation in vivo: unstressed SHR do not show elevated hsp70 expression even though their basal blood pressures (150 mm Hg) are sufficient to induce the response in WKY rats. However, SHR do show induction with treatments such as restraint, which further elevate their blood pressure above basal levels. Thus, it appears that it is not the absolute blood pressure attained but rather acute fluctuations in blood pressure above basal levels that are responsible for hsp70 induction in aorta.

HSP70 induction in response to restraint is attenuated in old rats.¹³ The present study offers an explanation for this attenuation, ie, that old rats show a lesser hsp70 response because their blood pressure does not become elevated in response to restraint. Why blood pressure does not increase in the old rats during restraint remains to be determined. However, it is important to point out that this is not because they do not perceive restraint to be stressful, because in previous studies we measured plasma levels of the stress hormone corticotropin in old and young rats during restraint and found it to be similar.¹³ Instead, we suggest that aging is accompanied by a reduced responsiveness of the peripheral vasculature to ₁-adrenergic stimulation. A number of studies have provided evidence for altered adrenergic function with age.^{25 26} Furthermore, in recent studies in which we have transplanted old vessels into young rats we have obtained evidence that the loss of responsiveness can be rescued, at least partially, by such transplantation. Likewise, we have observed that transplantation of young vessels to old rats leads to a diminished response.²⁷ These findings suggest that the environment in which the aorta resides is important in controlling hsp70 induction. Our proposed model for restraint-induced aortic hsp70 expression as well as age-related differences in responsiveness of the peripheral vasculature would account for our findings with transplanted vessels. Importantly, we have also shown that high doses of the hypertensive agents used in the present study increase blood pressure in the old rat, and this is associated with the induction of hsp70. Even with pharmacological doses of phenylephrine, however, the elevation in blood pressure was less in old rats compared with young adult rats, supporting the hypothesis that responsiveness to ₁-adrenergic agents declines with age. Finally, we and others^{2 28 29} have provided evidence for a general age-related decline in the DNA binding activity of the heat-shock transcription factor HSF1, which mediates the transcriptional activation of hsp70 in response to stress. While we have not addressed HSF1 activity in aortic tissue, it is likely that such differences in HSF1 activity could also contribute to reduced vascular hsp70 expression with age.

Many factors, ranging from physical exertion to drug toxicity, noise, or emotional stress, lead to a rise in blood pressure^{30 31} that under certain circumstances can lead to severe damage to the vessel wall or even rupture.^{32 33} Our demonstration that hsp70 expression is markedly increased during acute hypertension suggests a likely role for hsp70 in the host's defense to such hemodynamic stress.

	Acknowledgments

 
This work was supported in part by the George H.A. Clowes Jr Memorial Research Award of the American College of Surgeons and National Institutes of Health grant NIDDK, DK02064-04 (R.U.).

	Footnotes

 
Section on Gene Expression and Aging (Q.X., N.J.H.), National Institute on Aging, National Institutes of Health, and Division of Endocrine Surgery (D.L., R.U.), The Johns Hopkins Hospital, Baltimore, Md.

Received January 30, 1995; accepted February 27, 1995.

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