Biomedical subjects

F W Keeley

Publications and source records attributed to F W Keeley.

At least 37 records · Page 2Linked to original sources

PubMed1995

The appearance of proopiomelanocortin early in vertebrate evolution: cloning and sequencing of POMC from a Lamprey pituitary cDNA library.

A proopiomelanocortin (POMC)-like hormone has been cloned and sequenced from a pituitary cDNA library of upstream migrant (prespawning) sea lamprey, Petromyzon marinus. The clone, designated LPP-1, consisted of 986 nucleotides, with an open reading frame of 277 amino acids, including a signal peptide of 22 amino acids. Like POMCs from more recently evolved vertebrates, lamprey POMC contained domains which corresponded to alpha-MSH, ACTH, and beta-endorphin. However, sequences corresponding to gamma- and beta-MSH are absent or likely nonfunctional, respectively, in this cDNA. Northern blot analyses showed low but detectable expression levels of LPP-1 in larvae and strong expression in parasitic adults and prespawning animals. These observations indicate that a recognizable POMC, distinct from proenkephalin, has an ancient lineage within subphylum Vertebrata, likely dating back to the last common ancestor of the lamprey and gnathostome lines.

Adrenocorticotropic Hormone↗

PubMed1995

Decreased elastin synthesis in normal development and in long-term aortic organ and cell cultures is related to rapid and selective destabilization of mRNA for elastin.

We have previously shown that aortic organ cultures from 1- to 3-day-old chickens initially mimic the high levels of elastin production seen in vivo. However, more prolonged incubation of these tissues results in decreased synthesis of elastin. In the present study, we demonstrate that decreased production of elastin in these aortic organ cultures is selective for elastin compared with collagen and is correlated with decreased steady state levels of mRNA for elastin. These decreases in steady state levels of elastin mRNA are due at least in part to a rapid and selective destabilization of mRNA for elastin, the half-life of which falls from approximately 25 hours in fresh aortic tissues to approximately 15 hours after incubation for only 8 hours. Destabilization of elastin mRNA can be prevented by incubation in the presence of blockers of DNA transcription (5,6-dichlorobenzimidazole riboside and actinomycin D) and mRNA translation (cycloheximide). Furthermore, the half-life of aortic elastin mRNA decreases from approximately 25 hours in the 1-day-old chicken to approximately 7 hours in the 8-week-old chicken, demonstrating that destabilization of mRNA is an important contributing factor in the decline in production of aortic elastin taking place during normal postnatal growth.

Age Factors↗

PubMed1994

Serum-induced vascular smooth muscle cell elastolytic activity through tyrosine kinase intracellular signalling.

In previous studies, we related increased elastolytic activity in pulmonary arteries (PA) with endothelial injury to the later development of PA hypertension in rats. As the mechanism causing the increased PA elastase was unknown, we hypothesized that serum factors which are accessible to vascular smooth muscle cells (SMC) following endothelial injury stimulate their elastolytic activity. To test this, we developed an in vitro assay in which we added [3H]-elastin to cultured vascular SMC after 24 h serum starvation and monitored elastolysis following a further 24 h incubation with fetal bovine serum (FBS). We observed that serum induced increased elastolytic activity in both PA and aorta-derived SMC but not in endothelial cells or SMC with low basal levels of elastolytic activity. Maximum stimulation of SMC elastolytic activity occurred with a concentration as low as 1% FBS and despite elastase inhibitors in serum, suggesting that the activity is confined to the immediate pericellular region where enzyme concentration is high. Serum-stimulated elastolytic activity was not reproduced by growth factors or cytokines known to be associated with vascular disease or to induce release of elastases in other cells. The serum inducing elastolytic activity was heat and acid labile. It was associated with increased elastin adhesion to the 67 kD elastin binding protein on SMC surfaces and was prevented by tyrosine kinase inhibitors but not protein kinase C or A inhibitors. Our studies therefore suggest a mechanism whereby serum induction of SMC elastase requires signalling through the elastin binding protein and activation of tyrosine kinase.

Animals↗

PubMed1994

Pulmonary hypertension and vascular remodeling in fetal sheep.

Vascular remodeling is commonly associated with pulmonary hypertension (PH) postnatally, but little is known about its presence in fetuses. In sixteen fetal sheep (126 wk gestation), the ductus arteriosus (DA) was ligated, and the animals were studied at 4, 8, and 14 days after surgery. The uninstrumented twins served as controls. Four days post-DA ligation PH resulted in an increase in the right and left ventricular free wall weight ratio (1.2 +/- 0.1 vs. 1.0 +/- 0.1 in the controls; P < 0.01), with a further progressive increase at 8 (1.4 +/- 0.1 vs. 1.0 +/- 0.1; P < 0.01) and 14 days (1.5 +/- 0.2 vs. 1.0 +/- 0.1; P < 0.01). An increase in vascular percent medial thickness was observed after 4 days of DA ligation and was restricted to small vessels. The large arteries collagen and elastin contents were 28.9 +/- 3.4 and 27.1 +/- 3.4 micrograms/micrograms of DNA, respectively, and were not significantly different from control values even after 14 days DA ligation. We further compared elastin synthesis in fetal and neonatal arteries in vitro. Synthesis in the fetus was greater than the newborn (10.6 +/- 1.4 vs. 4.6 +/- 0.7 cpm.mg wet wt-1.h-1; P < 0.01). Vessel endothelium denudation reduced synthesis to 60 +/- 8% of controls in the fetus, whereas no change was seen in the newborn. After an increase in wall stress, synthesis increased in the fetus (194 +/- 28% of control P < 0.01) and newborn (173 +/- 25%; P < 0.01). Removal of the endothelium abolished the response.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Perinatal accumulation of arterial wall constituents: relation to hemodynamic changes at birth.

We compared arterial growth to hemodynamic changes in the perinatal period in lambs. Blood pressure did not change significantly from 120 days gestation to 3 days postpartum, when it was 45.4 +/- 1.9 mmHg; however, pressure rose to 64.8 +/- 2.5 mmHg at 21 days postpartum. Thoracic and abdominal aortic and iliac and carotid arterial blood flows fell > 50% after birth but returned to fetal levels except in the abdominal aorta by 21 days postpartum. Blood flows in mesenteric (BFm) and renal (BFr) arteries increased between 120 days gestation (BFr = 13.4 +/- 1.4; BFm = 41.8 +/- 3.5 ml/min) and 140 days gestation (BFr = 25.9 +/- 1.8; BFm = 189 +/- 18 ml/min) and between 3 and 21 days postpartum (to BFr = 71.1 +/- 14.3; BFm = 334 +/- 59 ml/min). Elastin accumulation accelerated at 140 days gestation in all arteries except the thoracic aorta, in which elastin accumulation was always rapid. Collagen but not DNA accumulation also accelerated in most arteries. Postpartum dexamethasone (0.1 mg/kg twice a day) did not affect abdominal aortic elastin by 10 days of age (23.9 +/- 2.7 vs. 26.4 +/- 4.1 mg for controls); however, dexamethasone upregulated tropoelastin mRNA in fetuses. We hypothesize that cortisol stimulates elastin accumulation in late gestation. Postnatal elastin but neither collagen nor DNA correlated with blood flow changes at birth (r = 0.855, P < 0.05). We infer that accumulation of elastin is sensitive to blood flow rates during perinatal development.

Animals↗

PubMed1994

The renin-angiotensin system and volume overload-induced changes in cardiac collagen and elastin.

BACKGROUND: Besides cardiac load, the renin-angiotensin system (RAS) and aldosterone may regulate collagen accumulation during maturation or hypertrophic growth. The effect of cardiac volume overload on both left ventricular (LV) and right ventricular (RV) collagen and elastin and the possible role of the RAS in such changes have not yet been assessed. METHODS AND RESULTS: In the present study we assessed (1) the effects of 4 to 10 weeks of volume overload by an aortocaval shunt or minoxidil on LV and RV collagen and elastin and (2) the potential of the angiotensin-converting enzyme inhibitor enalapril and the angiotensin II receptor blocker losartan to prevent and regress volume overload-induced changes in cardiac collagen and elastin. Cardiac volume overload by aortocaval shunt or minoxidil treatment decreased LV collagen accumulation as compared with control rats. In contrast, RV collagen accumulation was potentiated during the initial weeks but not during chronic aortocaval shunt. Enalapril and losartan prevented the relative decreases in LV collagen content and concentration induced by a shunt. Losartan also reversed the decrease in LV collagen content by aortocaval shunt. Neither blocker significantly affected the enhanced RV collagen accumulation during the initial weeks of shunt, but both blockers further potentiated RV collagen accumulation during chronic volume overload. Aortocaval shunt for 4 weeks but not 10 weeks enhanced LV and RV elastin accumulation. This initial increase in LV and RV elastin content was blocked by both enalapril and losartan. CONCLUSIONS: Cardiac volume overload, even when accompanied by increased plasma renin activity, decreases LV collagen accumulation, suggesting that in contrast to the stimulatory effect of systolic wall stress, increased diastolic wall stress inhibits collagen accumulation. In support of this concept, enalapril and losartan decreased LV preload and maintained LV collagen accumulation. In contrast to LV collagen, RV collagen accumulation was potentiated during the initial weeks of volume overload, possibly related to acute RV pressure overload shortly after aortocaval shunt and its decrease with chronic shunt. Enalapril and losartan had minimal effect on the enhanced RV collagen during the initial weeks of aortocaval shunt but potentiated RV collagen during chronic shunt, possibly by decreasing RV diastolic pressures. Altogether, these data suggest that during cardiac volume overload, the RAS affects cardiac collagen primarily by its hemodynamic effects. The RAS, however, may potentiate RV and LV elastin accumulation during the initial weeks of volume overload since both enalapril and losartan block this increase.

Aging↗

PubMed1994

Extracellular matrix remodeling after balloon angioplasty injury in a rabbit model of restenosis.

Remodeling of the vessel wall after balloon angioplasty injury is incompletely understood, and in particular, the role of extracellular matrix synthesis in restenosis has received little attention. The objective of the present study was to determine the sequence of changes in collagen, elastin, and proteoglycan synthesis and content after balloon injury and to relate these changes to growth of the intimal lesions and extent of cell proliferation. In a double-injury non-cholesterol-fed model, right iliac arterial lesions in 43 rabbits were treated with balloon angioplasty, and the rabbits were killed at five time points ranging from immediate to 12 weeks. Vessel wall collagen and elastin content and synthesis were measured after incubation with 14C-proline and separation with a cyanogen bromide extraction procedure. Sulfated glycosaminoglycan synthesis was measured after incubation with [35S]sulfate, papain digestion, and ethanol precipitation. Continuous in vivo infusion of bromodeoxyuridine (96 hours) was used to assess cell proliferation. The intimal area significantly increased from 0.27 +/- 0.08 to 0.73 +/- 0.11 mm2 between 0 and 12 weeks. Intimal and medial cell proliferation were modest and peaked at 1 week (labeling indexes of 4.8% and 3.0%, respectively) and then markedly declined by 2 weeks. Significant increases in collagen, elastin, and proteoglycan synthesis, up to 4 to 10 times above control nondamaged contralateral iliac arteries, were noted at 1, 2, and 4 weeks. These increases in synthesis were accompanied by significant increases in collagen and elastin content (by approximately 35%) that coincided with the temporal increase in cross-sectional area.(ABSTRACT TRUNCATED AT 250 WORDS)

Angioplasty, Balloon↗

PubMed1994

The endogenous vascular elastase that governs development and progression of monocrotaline-induced pulmonary hypertension in rats is a novel enzyme related to the serine proteinase adipsin.

We showed previously a cause and effect relationship between increased activity of an endogenous vascular elastase (EVE) and experimentally induced pulmonary hypertension in rats. We now report the isolation and characterization of EVE. Degenerate oligonucleotides synthesized to homologous sequences in serine elastases were used in a PCR with rat pulmonary artery (PA) cDNA. The PCR product hybridized to a 1.2-kb mRNA and the intensity of hybridization was threefold increased in RNA from rat hypertensive PA at a timepoint when EVE activity was increased. The PCR product was used to screen a cDNA library and sequences obtained encoded rat adipsin. We then used immunoaffinity to purify EVE. An antibody to the elastin-binding protein was used to remove this competitor of elastase from the PA extract and the elastolytic activity increased 100-fold. The enzyme was purified using an antibody that recognizes NH2-terminal sequences of serine proteinases and the eluate was further purified using an antibody raised against recombinant adipsin. A single band at 20 kD immunoreactive with the adipsin antibody was resolved as an active enzyme on an elastin substrate gel. Immunogold labeling with an antibody to an adipsin peptide sequence localized EVE to PA smooth muscle cells. This is the first isolation of EVE; it appears to be a novel enzyme related to the serine proteinase adipsin originally found in adipose tissue.

Amino Acid Sequence↗

PubMed1994

Biologic resurfacing of a major joint defect with cryopreserved allogeneic periosteum under the influence of continuous passive motion in a rabbit model.

Periosteal autografts have been widely used for biologic resurfacing of full-thickness articular cartilage defects in rabbits. This study examined the effect of donor and recipient age on biologic joint resurfacing using fresh and cryopreserved periosteal allografts in a rabbit model. The study also assessed the ability of cryopreserved periosteal allografts to undergo neochondrogenesis. Eighty New Zealand rabbits were divided into six groups receiving combinations of fresh or cryopreserved allografts. After all the grafts were secured with fibrin glue, the animals were subjected to two weeks of continuous passive motion followed by four weeks of cage activity or intermittent active motion. The rabbit knees were analyzed at six weeks by gross examination, histochemical staining, and collagen typing. No significant difference in chondrogenic potential between fresh and cryopreserved periosteal allografts was observed. Grafts obtained from adult donors were much less chondrogenic than those from adolescents, but adults recipients experienced reasonably good results when they received allografts from young donors. No evidence of rejection was found in any of the samples as late as six weeks after transplantation.

Aging↗

PubMed1993

Characterization of lamprin, an unusual matrix protein from lamprey cartilage. Implications for evolution, structure, and assembly of elastin and other fibrillar proteins.

Lamprin, an insoluble non-collagen, non-elastin protein, is the major connective tissue component of the fibrillar extracellular matrix of lamprey annular cartilage. Here we demonstrate that the soluble monomer of lamprin is a family of highly hydrophobic, self-aggregating proteins with molecular masses of 12 and 10 kDa. Two mRNAs for soluble lamprin were identified (0.9 and 2 kilobases), differing principally in the length of their 3'-untranslated tails. Variants of soluble lamprin appear to arise both as the products of multiple genes and by alternate splicing. Although not generally homologous to any other protein, soluble lamprins contain a tandemly repeated peptide sequence (GGLGY) which is present in both silkmoth chorion proteins and spider dragline silk. Strong homologies to this repeat sequence are also present in several mammalian and avian elastins. Monoclonal antibodies to VGVAPG, a repeated sequence in human elastin, also cross-react with lamprin. We suggest that these proteins share a structural motif which promotes self-aggregation and fibril formation in proteins through interdigitation of hydrophobic side chains in beta-sheet/beta-turn structures, a motif that has been preserved in recognizable form over several hundred million years of evolution.

Amino Acid Sequence↗

PubMed1993

Cryopreservation of periosteum for transplantation.

The concept of biological joint resurfacing has been widely studied, with encouraging results to date in both animal and human experiments. Most investigators have studied autograft tissue, however, in the clinical setting, situations might arise where autografting would not be suitable. We were therefore interested in developing a method of storing allograft periosteal tissue for biological joint resurfacing. A total of 192 periosteal grafts were harvested from 48 New Zealand White rabbits using sharp dissection (to include the cambium layer of progenitor cells). The free grafts were placed in a culture medium containing the cryopreservative dimethyl sulfoxide, then cooled at a controlled rate in a programmable freezer at rates of -0.5, -1.0, -2.0, or -10.0 degrees C/min. Viability of the grafts was assessed upon thawing after frozen storage for 8 days or 4 months using autoradiography and radioactive isotope uptake into newly synthesized proteins. Fresh, noncryopreserved and killed grafts were used as controls. A rate of cooling of -1.0 degrees C/min yielded viability results that were not significantly different from those of fresh controls. Furthermore, there was no change in viability as measured by radioactive isotope uptake over 4 months of storage. These results indicate that cryopreservation is a simple and efficient means of storing periosteal tissue for up to 4 months.

Animals↗

PubMed1993

Fetal bone gap healing in utero.

The healing of fetal tibial bone after osteotomy with and without stable fixation has been reported previously. The present study was designed to evaluate fetal bone gap healing using a tibial ostectomy model in fetal sheep. Eighteen time-dated pregnant ewes (20 fetuses, 34 experimental hind limbs) underwent intrauterine surgery at 95 days gestation (term, 145 days). A titanium miniplate was applied to the anterior aspect of the tibia and a longitudinal length of bone approximately 1.5 times its diameter was removed and the incision closed. The pregnancies were then allowed to progress until the ewe was killed at postoperative weeks 1, 2, 4, or 7. Assessments at that time included evaluation of gross morphology, histologic and radiologic appearance, and collagen analysis and hydroxyproline determination of the tissue within and at the borders of the gap. At 7 weeks, seven of nine bone gap specimens exhibited radiographic and histologic evidence of union with woven and lamellar bone. Hydroxyproline concentrations gradually increased within the bone gap over the period of the study. At all intervals, type I collagen composed over 90% of the collagen within the healing bony gap. Histologically and biochemically, the process appears to be similar to postnatal bone healing, albeit occurring at an accelerated rate.

Animals↗

PubMed1993

Relative efficiency of incorporation of newly synthesized elastin and collagen into aorta, pulmonary artery and pulmonary vein of growing pigs.

It is generally accepted that, once laid down in the extracellular matrix, elastin turns over only very slowly if at all. However, much of the evidence for minimal turnover of elastin comes from aortic tissue. In this study we have compared the relative synthesis rates of elastin and collagen with their relative accumulation rates in segments of aorta (AO), pulmonary artery (PA), and pulmonary vein (PV) of young, growing pigs. While rates of elastin synthesis are comparable in the AO and PA, the PA accumulates only 33% of the elastin deposited in the AO. Similarly, while the rate of elastin synthesis in the PV is 60% of that in the AO, accumulation of elastin is only 20% of that in the AO. Similar discrepancies between collagen synthesis and accumulation were seen among these three vessels. These data suggest that, at least in growing animals, the efficiency of permanent incorporation of elastin and collagen into the extracellular matrix may be an important factor in determining the final contents of these connective tissue proteins in vascular tissues.

Aging↗

PubMed1993

A developmentally regulated program restricting insolubilization of elastin and formation of laminae in the fetal lamb ductus arteriosus.

BACKGROUND: The ductus arteriosus (DA) is a fetal vessel in which the elastic laminae fail to assemble normally in late gestation. This feature is associated with the development of intimal cushions, structures that partially occlude the DA lumen and assure that the vessel will close completely when it constricts postnatally. EXPERIMENTAL DESIGN: We studied the fetal lamb DA at two different gestational time-points, 100 days before, and 138 days coincident with intimal cushion formation (term = 145 days) to establish the ultrastructural basis for the 'disassembly' of elastic laminae apparent on light microscopy and to determine further whether the mechanism was due to increased elastolytic activity, decreased synthesis of tropoelastin, or impaired insolubilization of tropoelastin. RESULTS: Morphometric ultrastructural analyses of tissue from the 138-day gestation fetal lambs revealed that the volume density of elastin in the DA vessel wall was only 40% of that in the aorta (Ao) and 50% of that in the pulmonary artery (PA). Moreover, only 16% of the elastin present contributed to the formation of laminae when compared to 80% in the Ao and 50% in the PA. Despite the morphologic appearance of 'fragmented' elastin, there was no evidence of increased elastolytic activity in the DA at either gestational time-point as judged by solubilization of a [3H] elastin substrate. The reduced elastin apparent was morphologically accompanied by an increase in soluble (tropo) elastin in DA compared with Ao and PA, as measured by enzyme linked immunosorbent assay, in tissue from both 100- and 138-day gestation lambs. Lack of differences in tropoelastin mRNA levels when comparing the 3 vessels suggested that the enzyme linked immunosorbent assay measurements reflected increased DA tropoelastin accumulation owing to lack of insolubilization rather than an increase in synthesis. Reduced insolubilization of newly synthesized elastin was evident in the DA compared with the Ao at 100 days gestation and in the DA compared with both Ao and PA at 138 days gestation in association with reduced desmosine levels. CONCLUSIONS: The mechanism of the decrease in tropoelastin insolubilization was unrelated to lysyl oxidase activity in the tissue and represents a unique developmental program.

Animals↗

PubMed1993

Fetal tibial bone healing in utero: the effects of miniplate fixation.

Although clinical and experimental findings have demonstrated that fetal soft-tissue wounds heal without scarring, very little is known about the process of fetal bone healing. This study examined fetal long bone healing in utero, both histologically and biochemically, with and without fracture fixation in a fetal sheep model. Our study group consisted of 25 live fetuses (from 16 ewes). There were 50 fetal tibias in this group; 12 were control, 17 were fixed (miniplate fixation), and 21 were nonfixed. A midshaft osteotomy of the tibia, either fixed or non-fixed, was performed on fetal sheep at 95 days' gestation (term = 145 days) in utero. The sheep were then killed at one of five postoperative time intervals (weeks 1, 2, 3, 4, and 7), and fetal bone healing was examined. The variables reviewed included gross morphology, histology, radiology, and collagen analysis (proportions of types II to I and III to I collagen). Fetal bone healing without fixation was accompanied by a large callus with rapid and abundant cartilage and collagen deposition. Bone healing was characterized by malunion or nonunion at 7 weeks. However, with miniplate and screw fixation, callus formation was minimal; primary bone healing occurred by 3 weeks and did not adversely affect long bone growth. Analysis of callus samples revealed a minimal amount of type III collagen, whereas the proportion of type II collagen was variable and proportional to the content of callus cartilage.

Animals↗

PubMed1992

Enalapril suppresses normal accumulation of elastin and collagen in cardiovascular tissues of growing rats.

We have investigated the effect of enalapril, an angiotensin converting-enzyme (ACE) inhibitor, on the accumulation of ventricular and vascular collagen and elastin in young, growing rats. Beginning at either 4 or 10 wk of age, male Wistar rats were treated with enalapril for 2 or 5 wk. Enalapril treatment had no significant effect on body weight and small, generally non-significant effects on systolic and diastolic blood pressures. In contrast, young enalapril-treated animals showed a marked decrease in accumulation of total elastin and collagen in both large (aorta, renal, and carotid) and smaller (superior and large mesenteric) arteries, as well as a large reduction in total collagen in both left and right ventricles. This effect also was present but less pronounced in rats treated with enalapril beginning at 10 wk of age. These data indicate that inhibition of ACE activity during a period of rapid growth significantly reduces accumulation of vascular and ventricular connective tissue and suggests that angiotensin II may be important in normal cardiovascular development and growth.

Aging↗

PubMed1992

Increased pulmonary artery elastolytic activity in adult rats with monocrotaline-induced progressive hypertensive pulmonary vascular disease compared with infant rats with nonprogressive disease.

In a rat model of pulmonary hypertension induced by monocrotaline, medial hypertrophy of the pulmonary arteries is associated with enhanced production (synthesis) of insoluble elastin relative to accumulation and an increased number of elastin fragments, features suggestive of an elastolytic process. In the present study, we measured and characterized pulmonary artery (PA) elastolytic activity at time points before as well as coincident with the progression of medial hypertrophy in monocrotaline-injected adult male Sprague-Dawley rats. We also determined whether medial hypertrophy is preceded by ultrastructural changes in elastin. Since medial hypertrophy develops but fails to progress in rats injected with monocrotaline at 8 days of age, we assessed whether, compared with adult rats, there were also structural and biochemical differences in elastin and elastolytic activity. A twofold increase in elastolytic activity per milligram tissue was observed 2 days after monocrotaline injection in adult rats (p less than 0.01), and there was an increased number of breaks in the internal elastic lamina (IEL) at 4 days (p less than 0.05) (i.e., before the development of medial hypertrophy). Associated with the progression of medial hypertrophy between 16 and 28 days after monocrotaline injection, there was a further threefold increase in elastolytic activity per milligram tissue by 28 days (p less than 0.01). Susceptibility of the elastolytic activity to specific inhibitors suggested that one or more serine elastases is involved. In infant rats in which medial and right ventricular hypertrophy fail to progress in severity between 16 and 28 days after monocrotaline injection, we did not measure an increase in elastolytic activity, nor was there evidence of an increase in the number of breaks in the IEL at 4 days, suggesting a lack of increased elastolytic activity at an earlier time point. The total content of PA elastin in infant rats, although increased compared with control rats (p less than 0.01), was not associated with heightened production and appeared ultrastructurally as thicker laminae (p less than 0.05) rather than as fragments previously reported in adult rats.

Age Factors↗

PubMed1991

Effects of antihypertensive drug classes on regression of connective tissue components of hypertension.

Hypertension leads to structural and functional adaptations which, although initially protective for the cardiovascular system, ultimately work to sustain and reinforce the hypertensive state. Although blood pressure (BP) may be effectively lowered by a variety of treatments, it is becoming clear that these structural adaptation, and the risks and consequences of hypertension, may persist long after BP has been restored to normal levels. Cardiovascular tissues appear to be highly sensitive to increased BP, responding quickly with large and proportional increases in collagen and elastin. The sensitivity of this response to increased pressure, together with the slow turnover of these connective tissue proteins, suggests a mechanism by which transient or intermittent episodes of hypertension may lead to cumulative and persistent structural changes in cardiovascular tissues. With some exceptions, studies directly investigating the reversibility of these connective tissue changes have generally confirmed that increased cardiovascular collagen and elastin persist for long periods of time after BP lowering, independent of the treatment method used to achieve that lowering. Because maintenance of elevated levels of collagen and elastin is principally caused by the slow turnover of the proteins rather than by their continued production, rapid and effective reversal of cardiovascular connective tissue changes may require the development of pharmacological agents that promote or accelerate the turnover of these proteins.

Animals↗