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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Smooth muscle cell differentiation and proliferation are increasingly seen to be intimately tied to the etiology of atherosclerosis and hypertension. To determine the role of PKC alpha in the regulation of smooth muscle cell differentiation and proliferation, the rat embryonic smooth muscle cell line A7r5 was transfected with an expression vector containing the full-length PKC alpha cDNA. Neomycin-resistant clones which exhibited increased PKC alpha levels compared to wild-type cells were selected. The A7r5 cells overexpressing PKC alpha had altered morphology and decreased growth rates compared to wild-type cells and cells transfected only with the neomycin resistance gene. Electrophoretic mobility shift assays showed that nuclear extracts from overexpressing clones gave a different pattern of protein-DNA binding to an AP-1 consensus oligonucleotide compared to wild-type cells. In contrast to the growth characteristics of these clones, their levels of cell differentiation marker proteins such as vinculin and desmin were not affected by PKC alpha overexpression. Moreover, the smooth muscle-specific differentiation marker alpha-actin was markedly reduced, while beta-actin levels were found to remain unchanged. Northern blot analysis confirmed that alpha-actin downregulation occurred at the RNA level. Western blot analysis revealed that A7r5 cells have five different PKC isoforms and that these isoform protein levels were not changed by PKC alpha overexpression. These findings suggest that PKC alpha regulates growth and differentiation of A7r5 smooth muscle cells and that these changes might result from altered expression/function of AP-1 transcription factors.
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PMID:Effects of protein kinase C alpha overexpression on A7r5 smooth muscle cell proliferation and differentiation. 934 91

Oleic acid and angiotensin II (Ang II) are elevated and may interact to accelerate vascular disease in obese hypertensive patients. We studied the effects of oleic acid and Ang II on growth responses of rat aortic smooth muscle cells (VSMCs). Oleic acid (50 micromol/L) raised thymidine incorporation by 50% at 24 hours and cell number by 55% at 6 days (P<.05). Ang II (10(-11) to 10(-6) mol/L) did not significantly increase thymidine incorporation or VSMC number. Combining Ang II and 50 micromol/L oleic acid doubled thymidine incorporation and VSMC number. Losartan, an angiotensin type 1 (AT1) receptor antagonist, blocked the synergistic interaction between Ang II and oleic acid, whereas the AT2 receptor antagonist PD 123319 did not. Protein kinase C inhibition and downregulation, as well as inhibition of extracellular signal-regulated kinase (ERK) activation by PD 98059, eliminated the rise of thymidine incorporation in response to oleic acid and the synergistic interaction with Ang II. However, the response to 10% fetal bovine serum was unaffected. An antisense oligodeoxynucleotide to ERK-1 and ERK-2 reduced ERK protein expression and activation by 83% and 75%, respectively. Antisense prevented the rise of thymidine incorporation in response to oleic acid and the synergy with Ang II. Antisense reduced but did not prevent increased thymidine incorporation in response to serum. The data indicate that oleic acid and Ang II exert a synergistic mitogenic effect in VSMCs and suggest an important role for the AT1 receptor, PKC, and ERK in this synergy. The observations raise the possibility that a synergistic mitogenic interaction between oleic acid and Ang II accelerates vascular remodeling in obese hypertensive patients.
Hypertension 1998 Apr
PMID:Oleic acid and angiotensin II induce a synergistic mitogenic response in vascular smooth muscle cells. 953 24

This article reviews related studies from the authors' laboratory, which focus on the regulation of vascular Na+,K+-ATPase in hypertension. Earlier studies, including the authors', suggested that Na-pump activity in cardiovascular tissues is subject to regulation during hypertension; most of these studies report a stimulation of the vascular enzyme during established stages of hypertension. To test hypothesis that in vascular smooth muscle, strain resulting from elevated pressure may be a signal initiating a cascade of events leading to increased expression of Na+,K+-ATPase, the authors used cell culture and the Flexercell Strain Unit to apply cyclical stretch to rat aortic smooth muscle cells (ASMC) for several days. These studies demonstrated that mechanical strain induces the upregulation of both the alpha-1 and alpha-2 subunits of Na+,K+-ATPase. Mechanisms underlying these changes appear to involve a transient increase in intracellular sodium entering the cell through stretch-activated channels. Calcium entering the cell via L-type channels did not affect stretch-induced upregulation of the alpha isoforms. In addition, protein kinase C inhibition resulted in inhibition of the Na-pump during stretch, but not under nonstretch conditions. The authors conclude that the stretch component of vascular pressure upregulates the Na+,K+-ATPase catalytic subunits. Intracellular sodium may be a signal for this regulation. In addition, phosphorylation by PKC may be important in stretch-induced short-term regulation of the vascular Na-pump.
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PMID:Effect of mechanical strain on expression of Na+,K+-ATPase alpha subunits in rat aortic smooth muscle cells. 974 62

Elevated levels of nerve growth factor (NGF) protein and NGF mRNA have been reported in the vessels of spontaneously hypertensive rats (SHR: hypertensive, hyperactive) compared to Wistar-Kyoto (WKY) rats. Elevated NGF may be involved in the development of hypertension in SHRs. We examined vascular NGF mRNA and protein content and the regulation of NGF secretion by vascular smooth muscle cells (VSMCs) from two inbred strains (WKHT: hypertensive; WKHA: hyperactive) derived from SHRs and WKYs. Our goal was to determine if receptor-mediated defects in NGF regulation play a role in increased secretion of VSMC NGF from hypertensive animals. Tissue NGF mRNA content was determined by competitive, quantitative RT-PCR. Tissue NGF and NGF content in cultured VSMC-conditioned medium was quantified using a two-site ELISA. Tail artery NGF mRNA was elevated in WKHTs compared to WKHAs. Tissue NGF protein was elevated in WKHT aorta, mesenteric, and tail artery compared to WKHAs. Pharmacologically induced increases in NGF output were blocked with inhibition of transcription or protein synthesis. Basal NGF secretion by WKHT VSMCs was significantly higher than WKHAs. The observed increases in VSMC NGF output in SHRs over WKYs in response to beta-adrenergic agents are not preserved in the WKHT:WKHA comparison. Protein kinase C-dependent increases in SHR VSMC NGF appear in both WKHTs and WKHAs. In contrast, elevated NGF levels due to disturbances in alpha-adrenergic, peptidergic, and purinergic control of NGF output are features common to both genetic models of hypertension (SHR and WKHT). These results suggest that the defect in smooth muscle NGF metabolism observed in SHRs cosegregates with a hypertensive rather than a hyperactive phenotype. Moreover, altered receptor-mediated regulation (alpha-adrenergic, peptidergic, and purinergic) of VSMC NGF production may contribute to elevated vascular tissue NGF, suggesting a mechanism leading to the high levels of NGF associated with hypertension in SHRs and WKHTs.
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PMID:Arterial nerve growth factor (NGF) mRNA, protein, and vascular smooth muscle cell NGF secretion in hypertensive and hyperactive rats. 977 Mar 62

We here review mechanisms that can regulate the activity of myosin II, in smooth muscle and non-muscle cells, by modulating the Ca2+ sensitivity of myosin regulatory light chain (RLC) phosphorylation. The major mechanism of Ca2+ sensitization of smooth muscle contraction and non-muscle cell motility is through inhibition of the smooth muscle myosin phosphatase (MLCP) that dephosphorylates the RLC in smooth muscle and non-muscle. The active, GTP-bound form of the small GTPase RhoA activates a serine/threonine kinase, Rho-kinase, that phosphorylates the regulatory subunit of MLCP and inhibits phosphatase activity. G-protein-coupled release of arachidonic acid may also contribute to inhibition of MLCP acting, at least in part, through the Rho/Rho-kinase pathway. Protein kinase C(s) activated by phorbol esters and diacylglycerol can also inhibit MLCP by phosphorylating and thereby activating CPI-17, an inhibitor of its catalytic subunit; this mechanism is independent of the Rho/Rho-kinase pathway and plays only a minor, transient role in the G-protein-coupled mechanism of Ca2+ sensitization. Ca2+ sensitization by the Rho/Rho-kinase pathway contributes to the tonic phase of agonist-induced contraction in smooth muscle, and abnormally increased activation of myosin II by this mechanism is thought to play a role in diseases such as high blood pressure and cancer cell metastasis.
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PMID:Signal transduction by G-proteins, rho-kinase and protein phosphatase to smooth muscle and non-muscle myosin II. 1063 96

The objectives of the present study were (1) to determine whether oxidized LDL and lysophosphatidylcholine (lyso-PtdCho), a major phospholipid component of oxidized LDL, stimulate the migration of cultured human mesangial cells and (2) to investigate the possible effects on mesangial cell migration of the cardiac natriuretic peptides atrial and brain natriuretic peptide (ANP and BNP). Oxidized LDL (10 and 100 microg/mL) and lyso-PtdCho (10(-7) to 10(-5) mol/L) stimulated migration in a concentration-dependent manner. In contrast, the effects of native LDL and phosphatidylcholine were modest or nonexistent. Protein kinase C (PKC) inhibitor and downregulation of PKC activity by phorbol ester inhibited oxidized LDL- and lyso-PtdCho-induced migration. Human ANP(1-28) and human BNP-32 significantly inhibited oxidized LDL- and lyso-PtdCho-induced migration in a concentration-dependent manner. C-ANF (des-[Glu(18),Ser(19),Gly(20),Leu(21),Gly(22)]ANP(4-23)), a specific ligand for ANP clearance receptors, could not inhibit oxidized LDL- and lyso-PtdCho-induced migration. Inhibition by ANP and BNP of lyso-PtdCho-induced migration was paralleled by an increase in the cellular level of GMP. Oxidized LDL- and lyso-PtdCho-induced migrations were inhibited by 8-bromo-cGMP. The results suggest that oxidized LDL and lyso-PtdCho stimulate the migration of human mesangial cells, at least in part, through a PKC-dependent process and that ANP and BNP inhibit this stimulated migration, probably through a cGMP-dependent process.
Hypertension 2000 Apr
PMID:Effects of cardiac natriuretic peptides on oxidized low-density lipoprotein- and lysophosphatidylcholine-induced human mesangial cell migration. 1077 71

The angiotensin type 1 receptor (AT(1)) exerts a variety of its signaling and cellular actions through its effects on protein phosphorylation. Phosphoproteomic analysis of angiotensin (Ang) II-stimulated aortic smooth muscle cells revealed that heat shock protein 27 (HSP27) represents a major protein phosphorylation target of the AT(1) signaling pathway. Stimulation of cells with Ang II resulted in 1.7-fold (P<0.05) and 5.5-fold (P<0.001) increases in HSP27 phosphoisoforms at pI 5.7 and pI 5.4, respectively. This was accompanied by a 54% (P<0.01) decrease in the nonphosphorylated HSP27 isoform, located at pI 6.4. Treatment of samples with alkaline phosphatase reversed this redistribution of HSP27 phosphoisoforms. Ang II-stimulated HSP27 phosphorylation was completely blocked by pretreatment of cells with the AT(1) antagonist CV11974. Phosphoamino acid analysis demonstrated that Ang II-induced phosphorylation of both HSP27 phosphoisoforms occurred exclusively on serine. Protein kinase C inhibition completely blocked phorbol ester-induced HSP27 phosphorylation but did not impair Ang II-stimulated phosphorylation of HSP27, suggesting that AT(1) increased HSP27 phosphorylation by a protein kinase C-independent pathway. Intrajugular infusion of Ang II in rats increased HSP27 in aorta by 1.7-fold (P<0.02), and this response was inhibited by CV11974. These results suggest that Ang II-induced HSP27 phosphorylation is a physiologically relevant AT(1) signaling event. Because serine phosphorylation of HSP27 blocks its ability to cap F-actin, Ang II/AT(1)-induced HSP27 phosphorylation may play a key role in actin filament remodeling required for smooth muscle cell migration and contraction.
Hypertension 2001 Dec 01
PMID:Angiotensin AT(1) receptor stimulates heat shock protein 27 phosphorylation in vitro and in vivo. 1175

Hypertension activates many endocrine, neuroendocrine and metabolic responses. How hypertension alters these functions remains unknown. Consequently the pathophysiology of hypertension related illnesses are incompletely understood. Protein kinase C (PKC) isoforms play an important role in cellular signal transduction and altered PKC activity has been reported in spontaneous hypertensive rats (SHR). In order to understand the role that PKC plays in hypertension, we hypothesized that PKC activity is significantly expressed in synaptosomal preparations from the brains of SHRs. In addition, the neuroanatomical distribution of this expression was mapped and compared to control animals. The brains were further studied for signs of neuropathology. Total PKC activity was significantly increased in synaptosomal samples isolated from the forebrain, midbrain, and hindbrain of SHR rats. Westem blot analysis identified PKC-alpha, -beta, -gamma, -delta, -epsilon and -zeta in all brain regions. Immunohistochemical analyses indicated that PKC-gamma was localized in cell bodies and processes in many autonomic cardiovascular control regions. These results suggest that PKC may be an important modulator of autonomic blood pressure control.
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PMID:Expression and distribution of protein kinase C isozymes in brain tissue of spontaneous hypertensive rats. 1178 60

We previously showed that CGP 42112 (an angiotensin type 2 [AT(2)] agonist) markedly reduces catecholamine biosynthesis by decreasing cGMP production mediated by AT(2), a subtype of Ang II receptor that is dominantly expressed in cultured porcine chromaffin cells. To elucidate the relationship of the 2 types of Ang II receptors, angiotensin type 1 (AT(1)) and AT(2), in the synthesis of catecholamine in adrenal medullary cells, we have examined the effect of Ang II plus CV-11974 (an AT(1) antagonist that selectively simulates AT(2) stimulation) and the effect of Ang II plus PD 123319 (an AT(2) antagonist that selectively simulates AT(1) stimulation) on catecholamine synthesis. We found that Ang II reduced cGMP production via AT(2), in a similar manner to that found with CGP 42112. Stimulation of AT(1) significantly upregulated protein kinase C activity. Tyrosine hydroxylase (TH) is a rate-limiting enzyme involved in the biosynthesis of catecholamine, and this catecholamine synthesis depends both on TH enzyme activity and on the levels of TH protein after TH gene transcription. We found that AT(2) stimulation significantly inhibited TH enzyme activity, whereas AT(1) stimulation significantly upregulated TH enzyme activity. The stimulatory effect of AT(1) was completely inhibited by Ro-32-0432 (a protein kinase C inhibitor) and PD 98059 (a MAP kinase kinase-1 [MEK-1] inhibitor). Pretreatment of cells with either 8-Br-cGMP (a membrane-permeable cGMP analog) or Zaprinast (a phosphodiesterase inhibitor) abolished the inhibitory effect of AT(2) on TH enzyme activity, indicating that the stimulatory effect of AT(2) may be mediated through a reduction in cGMP concentration. Similar to the effect on TH enzyme activity, AT(2) stimulation significantly reduced TH mRNA and protein levels and net catecholamine content below basal levels, whereas AT(1) stimulation increased them. We confirmed these findings by gel mobility shift assay. Our results show that stimulation of AT(2) reduces catecholamine biosynthesis via a decrease in cGMP levels. In contrast, stimulation of AT(1) stimulates catecholamine biosynthesis through activation of PKC. Thus, we conclude that AT(1) and AT(2) have counter-regulatory roles in the synthesis of catecholamine in adrenal medullary chromaffin cells.
Hypertension 2002 Jan
PMID:Angiotensin II type 2 receptor counter-regulates type 1 receptor in catecholamine synthesis in cultured porcine adrenal medullary chromaffin cells. 1179 93

Several vasoconstrictor agents can regulate the phosphorylation status of the Na(+)-K(+) ATPase (NKA). We have recently demonstrated that mammalian tissues contain an endogenous bufadienolide, digitalis-like alpha(1)-NKA-selective ligand, marinobufagenin (MBG). Protein kinase C induces phosphorylation of the alpha(1)-NKA isoform, the major isoform in vascular smooth muscle, kidney, and heart cells. We hypothesized that protein kinase C-induced phosphorylation of NKA can potentiate the effect of endogenous digitalis-like ligands, and that such potentiation can occur in an NKA isoform-specific fashion. A protein kinase C activator, phorbol 12,13-diacetate (PDA, 50 nmol/L), induced phosphorylation of the alpha1-NKA from human mesenteric artery (HMA) sarcolemma and rat kidney but not that of the alpha(3)-NKA from rat fetal brain. In HMA sarcolemma, which predominantly contains alpha(1)-NKA, PDA (50 nmol/L) potentiated the NKA-inhibitory effect of MBG at the level of high-affinity binding sites (0.05 +/- 0.03 nmol/L versus 4.0 +/- 1.7 nmol/L, P<0.05). In contrast, PDA did not affect the NKA inhibition by ouabain, an alpha(3)-NKA ligand. In isolated endothelium-denuded HMA artery rings, 50 nmol/L PDA potentiated the MBG-induced vasoconstriction (EC(50), 17 +/- 6 nmol/L versus 150 +/- 40 nmol/L; P<0.01). Our results suggest that alpha(1)-isoform-specific NKA inhibition by the endogenous digitalis-like ligand, MBG, is substantially enhanced via NKA phosphorylation by protein kinase C. Thus, an interaction of protein kinase C-dependent phosphorylation and MBG on NKA activity may underlie the synergistic vasoactive effects of MBG and other endogenous vasoconstrictors in hypertension.
Hypertension 2002 Feb
PMID:Phorbol diacetate potentiates na(+)-k(+) ATPase inhibition by a putative endogenous ligand, marinobufagenin. 1184 1


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