Overexpression of Gi-proteins precedes the development of DOCA-salt-induced hypertension: relationship with adenylyl cyclase

Marcil, Josée; Champlain, Jacques de; Anand‐Srivastava, Madhu B.

doi:10.1016/s0008-6363(98)00111-4

Cited by 56 publications

(41 citation statements)

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“…6 Furthermore, decreased Gs-protein function has been detected in hypertensive subjects, 29,30 and lower levels of Gs protein have been found in salt-induced hypertensive rats. 31 Upregulation of G␣q/11 and PKC␣ was only found in heart membranes of 2-OHOA-treated rats. Because an increase in cAMP levels as well as signal transduction through G␣q in the heart can lead to higher cardiac contractility via Ca 2ϩ and PKC activation, alterations in the levels of these signaling proteins could be considered a compensatory mechanism to avoid further BP reduction in rats.…”

Section: Discussionmentioning

confidence: 96%

2-Hydroxyoleic Acid

et al. 2004

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Abstract-Recent studies have shown that diets rich in monounsaturated fatty acids (MUFAs) from olive oil, a natural source of oleic acid, have beneficial effects on blood pressure (BP) in hypertensive patients. With this in mind, we investigated whether a synthetic derivative of the MUFA oleic acid, 2-hydroxyoleic acid (2-OHOA), was capable of regulating the BP of Sprague-Dawley rats. Intraperitoneal and oral administration of 2-OHOA to rats induced significant and sustained decreases in BP in a time-dependent manner. Without affecting heart rate, treatments for 7 days provoked reductions in systolic BP of 20 to 26 mm Hg. At the molecular level, the density of G␣s, but not G␣i 2 or G␣o, increased in membranes from the hearts and aortas of 2-OHOA-treated rats, whereas in heart membranes, the density of G␣q/11 and protein kinase C␣ proteins was also augmented. These molecular alterations were reflected in the increase in cAMP levels after G␣s protein and ␤-adrenergic receptor stimulation. On the contrary, inhibitory hormones reduced adenylyl cyclase activity to the same extent in 2-OHOA-treated rats as in vehicle-treated ones. Our results indicate that cardiovascular tissues from 2-OHOA-treated rats exhibited increased cAMP production in response to G␣s activation, which might be attributed to enhanced expression of G␣s proteins. As a result of this change, a significant reduction in systolic BP was observed. Therefore, BP can be lowered by administration of 2-OHOA, which might represent the first member of a new family of antihypertensive drugs. Key Words: blood pressure Ⅲ fatty acids Ⅲ signal transduction Ⅲ G proteins Ⅲ hypotension M any alterations in the structure and function of the cell membrane have been associated with hypertension. Changes in the plasma or membrane lipid composition have been reported in both hypertensive humans 1 and in animal models of hypertension. 2,3 These changes have been associated with abnormalities in cation transport systems, 4 cytosolic Ca 2ϩ regulation, 5 and impaired signal transduction. 6 As a result, it has been proposed that modifications of the membrane lipid composition can affect the physical and functional properties of membranes and in consequence, might account for the alterations in signaling implicated in the physiological control of blood pressure (BP). In this context, long-term fatty acid (FA) intake is known to influence both membrane lipid composition and BP. Olive oil, a natural source of the monounsaturated FA (MUFA) oleic acid, has been shown to have beneficial effects on BP (when high doses are consumed for long periods) and is associated with a low incidence of coronary heart disease. 7 Olive oil consumption causes favorable changes in plasma lipid and lipoprotein profiles 8,9 and also in the phospholipid content and FA composition of both erythrocyte membranes from hypertensive patients and aorta membranes from spontaneously hypertensive rats. 10,11 Moreover, a slight reduction in saturated fat intake along with the use of olive oil markedly lowers the ...

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Section: Discussionmentioning

confidence: 96%

2-Hydroxyoleic Acid

et al. 2004

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“…Accordingly, deficient AC activity in vascular cells, caused by altered G protein levels and function, diminishes intracellular cAMP levels, a hallmark of hypertension in humans (38,39) and in experimental animal models (30). Indeed, a rise in the expression of inhibitory G i proteins in the aorta of hypertensive animals precedes the development of high BP, which is probably a major contributory factor in the pathogenesis of hypertension (29,30,40,41). In addition, 2-hydroxyoleic acid regulates transient outward K ϩ current in cardiomyocytes, which might be associated with the cardioprotective effects of cis-MUFA (42).…”

Section: Molecular Mechanisms Involved In the Hypotensive Effects Of mentioning

confidence: 99%

“…In turn, this modification affects the docking of important membrane-associated signal transduction proteins involved in controlling BP, such as G proteins (1,24,25). In fact, altered levels and function of G proteins have been reported in both hypertensive humans (26,27) and experimental models of hypertension (28,29).…”

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confidence: 99%

Oleic acid content is responsible for the reduction in blood pressure induced by olive oil

Terés

Barceló‐Coblijn

Benet

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

433

266

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Numerous studies have shown that high olive oil intake reduces blood pressure (BP). These positive effects of olive oil have frequently been ascribed to its minor components, such as ␣-tocopherol, polyphenols, and other phenolic compounds that are not present in other oils. However, in this study we demonstrate that the hypotensive effect of olive oil is caused by its high oleic acid (OA) content (Ϸ70 -80%). We propose that olive oil intake increases OA levels in membranes, which regulates membrane lipid structure (HII phase propensity) in such a way as to control G protein-mediated signaling, causing a reduction in BP. This effect is in part caused by its regulatory action on G protein-associated cascades that regulate adenylyl cyclase and phospholipase C. In turn, the OA analogues, elaidic and stearic acids, had no hypotensive activity, indicating that the molecular mechanisms that link membrane lipid structure and BP regulation are very specific. Similarly, soybean oil (with low OA content) did not reduce BP. This study demonstrates that olive oil induces its hypotensive effects through the action of OA.aorta ͉ fatty acids ͉ membrane structure ͉ signaling proteins ͉ membrane-lipid therapy

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“…[15][16][17] The increased levels of G i␣ were shown to be associated with hypertension and not with hypertrophy, 21 whereas the decreased levels of G s␣ were associated with hypertrophy and not with hypertension. 22 We have recently shown that the increased expression of G i␣ proteins occurs before the onset of hypertension in SHR 23 and in DOCA-salt hypertensive rats, 24 suggesting that the enhanced levels of G i␣ proteins may be one of the contributing factors in the pathogenesis of hypertension. The present studies were undertaken to investigate the effect of inactivation of G i␣ protein by pertussis toxin (PT) treatment on the development of high BP in SHR.…”

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confidence: 99%

Inactivation of Enhanced Expression of G _i Proteins by Pertussis Toxin Attenuates the Development of High Blood Pressure in Spontaneously Hypertensive Rats

Anand‐Srivastava

2002

Circulation Research

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Abstract-We have previously shown that the enhanced expression of G i proteins in spontaneously hypertensive rats (SHR) that precedes the development of high blood pressure may be one of the contributing factors in the pathogenesis of hypertension. In the present study, we demonstrate that the inactivation of G i proteins by intraperitoneal injection of pertussis toxin (PT, 1.5 g/100 g body wt) into 2-week-old prehypertensive SHR prevented the development of hypertension up to 4 weeks and that, thereafter, it started to increase and reached the same level found in untreated SHR after 6 weeks. A second injection of PT after 4 weeks delayed the increase in blood pressure for another week. The PT-induced decrease in blood pressure in 6-week-old SHR was associated with a decreased level of G i␣ -2 and G i␣ -3 proteins in the heart, as determined by in vitro ADP ribosylation and immunoblotting. The decreased level of G i proteins was reflected in decreased G i functions. Furthermore, an augmentation of blood pressure to the same level in PT-treated SHR as found in untreated SHR was associated with enhanced expression and function of G i . These results indicate that the inactivation of G i proteins by PT treatment in prehypertensive SHR attenuates the development of hypertension and suggest that the enhanced levels of G i proteins that result in the decreased levels of cAMP and associated impaired cellular functions may be contributing factors in the pathogenesis of hypertension in SHR. Key Words: pertussis toxin Ⅲ ADP ribosylation Ⅲ G proteins Ⅲ blood pressure Ⅲ spontaneously hypertensive rats G uanine nucleotide regulatory proteins (G proteins) are a family of GTP-binding proteins that play an important role in the regulation of a variety of signal transduction systems, including the adenylyl cyclase/cAMP system. The adenylyl cyclase system is composed of three components: receptor, catalytic subunit, and stimulatory (G s ) and inhibitory (G i ) guanine nucleotide regulatory proteins. 1,2 The stimulation and inhibition of adenylyl cyclase by hormones are mediated by these two distinct G proteins (G s and G i , respectively), which couple the receptor to the catalytic subunit. The G proteins are heterotrimeric and are composed of ␣, ␤, and ␥ subunits. The ␣ subunits bind and hydrolyze GTP and confer specificity in receptor and effector interactions. Molecular cloning has revealed four different forms of G s␣ resulting from the differential splicing of one gene 3-5 and three distinct forms of G i␣ (G i␣ -1, G i␣ -2, and G i␣ -3) encoded by three distinct genes. 6 All three forms of G i␣ (G i␣ 1 to G i␣ 3) are implicated in adenylyl cyclase inhibition 6 and in the activation of atrial K ϩ channels. 7 The adenylyl cyclase/cAMP system has been implicated in both the control of heart contractility and vascular smooth muscle tone. 8,9 The levels of cAMP are regulated by G s and G i proteins. G i protein and associated adenylyl cyclase signaling has been shown to be implicated in a variety of cellular functions, including ...

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Overexpression of Gi-proteins precedes the development of DOCA-salt-induced hypertension: relationship with adenylyl cyclase

Cited by 56 publications

References 55 publications

2-Hydroxyoleic Acid

2-Hydroxyoleic Acid

Oleic acid content is responsible for the reduction in blood pressure induced by olive oil

Inactivation of Enhanced Expression of G _i Proteins by Pertussis Toxin Attenuates the Development of High Blood Pressure in Spontaneously Hypertensive Rats

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Overexpression of Gi-proteins precedes the development of DOCA-salt-induced hypertension: relationship with adenylyl cyclase

Cited by 56 publications

References 55 publications

2-Hydroxyoleic Acid

2-Hydroxyoleic Acid

Oleic acid content is responsible for the reduction in blood pressure induced by olive oil

Inactivation of Enhanced Expression of G i Proteins by Pertussis Toxin Attenuates the Development of High Blood Pressure in Spontaneously Hypertensive Rats

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Inactivation of Enhanced Expression of G _i Proteins by Pertussis Toxin Attenuates the Development of High Blood Pressure in Spontaneously Hypertensive Rats