scholarly journals Glucose-6-phosphate dehydrogenase increases Ca2+ currents by interacting with Cav1.2 and reducing intrinsic inactivation of the L-type calcium channel

2020 ◽  
Vol 319 (1) ◽  
pp. H144-H158 ◽  
Author(s):  
Rakhee Gupte ◽  
Vidhi Dhagia ◽  
Petra Rocic ◽  
Rikuo Ochi ◽  
Sachin A. Gupte
Keyword(s):  
Blood Pressure ◽  
Metabolic Syndrome ◽  
Smooth Muscle ◽  
Calcium Channel ◽  
Smooth Muscle Cell ◽  
Crucial Role ◽  
Vascular Function ◽  
Metabolic Enzyme ◽  
Glucose 6 Phosphate Dehydrogenase ◽  
Expression And Activity

In this study we have identified a novel isozyme of glucose-6-phosphate dehydrogenase (G6PD), a metabolic enzyme, that interacts with and contributes to regulate smooth muscle cell L-type Ca2+ ion channel function, which plays a crucial role in vascular function in physiology and pathophysiology. Furthermore, we demonstrate that expression and activity of this novel G6PD isoform are increased in arteries of individuals with metabolic syndrome and in inhibition of G6PD activity in rats of metabolic syndrome reduced blood pressure.

scholarly journals Vascular smooth muscle cell contractile protein expression is increased through protein kinase G-dependent and -independent pathways by glucose-6-phosphate dehydrogenase inhibition and deficiency

2016 ◽  
Vol 311 (4) ◽  
pp. H904-H912 ◽  
Author(s):  
Sukrutha Chettimada ◽  
Sachindra Raj Joshi ◽  
Vidhi Dhagia ◽  
Alessandro Aiezza ◽  
Thomas M. Lincoln ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Protein Kinase ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Vascular Smooth Muscle Cell ◽  
Contractile Proteins ◽  
Protein Kinase G ◽  
Glucose 6 Phosphate Dehydrogenase

Homeostatic control of vascular smooth muscle cell (VSMC) differentiation is critical for contractile activity and regulation of blood flow. Recently, we reported that precontracted blood vessels are relaxed and the phenotype of VSMC is regulated from a synthetic to contractile state by glucose-6-phosphate dehydrogenase (G6PD) inhibition. In the current study, we investigated whether the increase in the expression of VSMC contractile proteins by inhibition and knockdown of G6PD is mediated through a protein kinase G (PKG)-dependent pathway and whether it regulates blood pressure. We found that the expression of VSMC-restricted contractile proteins, myocardin (MYOCD), and miR-1 and miR-143 are increased by G6PD inhibition or knockdown. Importantly, RNA-sequence analysis of aortic tissue from G6PD-deficient mice revealed uniform increases in VSMC-restricted genes, particularly those regulated by the MYOCD-serum response factor (SRF) switch. Conversely, expression of Krüppel-like factor 4 (KLF4) is decreased by G6PD inhibition. Interestingly, the G6PD inhibition-induced expression of miR-1 and contractile proteins was blocked by Rp-β-phenyl-1, N2-etheno-8-bromo-guanosine-3′,5′-cyclic monophosphorothioate, a PKG inhibitor. On the other hand, MYOCD and miR-143 levels are increased by G6PD inhibition through a PKG-independent manner. Furthermore, blood pressure was lower in the G6PD-deficient compared with wild-type mice. Therefore, our results suggest that the expression of VSMC contractile proteins induced by G6PD inhibition occurs via PKG1α-dependent and -independent pathways.

scholarly journals Essential hypertension is associated with blunted smooth muscle cell vasodilator responsiveness and is reversed by 10-20-30 training in men

2020 ◽  
Vol 318 (6) ◽  
pp. C1252-C1263 ◽  
Author(s):  
Thomas P. Gunnarsson ◽  
Thomas S. Ehlers ◽  
Matteo Fiorenza ◽  
Michael Nyberg ◽  
Jens Bangsbo
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Essential Hypertension ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Vascular Function ◽  
Lower Limbs ◽  
Moderate Intensity ◽  
Nighttime Blood Pressure ◽  
Vascular Responsiveness

Essential hypertension is associated with impairments in vascular function and sympathetic nerve hyperactivity; however, the extent to which the lower limbs are affected remains unclear. We examined the leg vascular responsiveness to infusion of acetylcholine (ACh), sodium nitroprusside (SNP), and phenylephrine (PEP) in 10 hypertensive men [HYP: age 59.5 ± 9.7 (means ± SD) yr; clinical and nighttime blood pressure: 142 ± 10/86 ± 10 and 141 ± 11/83 ± 6 mmHg, respectively; and body mass index (BMI): 29.2 ± 4.0 kg/m2] and 8 age-matched normotensive counterparts (NORM: age 57.9 ± 10.8 yr; clinical and nighttime blood pressure: 128 ± 9/78 ± 7 and 116 ± 3/69 ± 3 mmHg, respectively; and BMI: 26.3 ± 3.1 kg/m2). The vascular responsiveness was evaluated before and after 6 wk of 10-20-30 training, consisting of 3 × 5 × 10-s sprint followed by 30 and 20 s of low- to moderate-intensity cycling, respectively, interspersed by 3 min of rest. Before training, the vascular responsiveness to infusion of SNP was lower ( P < 0.05) in HYP compared with NORM, with no difference in the responsiveness to infusion of ACh and PEP. The vascular responsiveness to infusion of SNP and ACh improved ( P < 0.05) with training in HYP, with no change in NORM. With training, intra-arterial systolic blood pressure decreased ( P < 0.05) by 9 mmHg in both HYP and NORM whereas diastolic blood pressure decreased (5 mmHg; P < 0.05) in HYP only. We provide here the first line of evidence in humans that smooth muscle cell vasodilator responsiveness is blunted in the lower limbs of hypertensive men. This impairment can be reversed by 10-20-30 training, which is an effective intervention to improve the responsiveness of smooth muscle cells in men with essential hypertension.

Abstract 310: Deoxycorticosterone Acetate (doca)-salt Exacerbates Hypertension and Vascular Dysfunction in Mice Expressing Dominant Negative Peroxisome Proliferator-activated Receptor-gamma (pparg) in Smooth Muscle

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Pimonrat Ketsawatsomkron ◽  
Deborah R Davis ◽  
Aline M Hilzendeger ◽  
Justin L Grobe ◽  
Curt D Sigmund
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Transgenic Mice ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Critical Role ◽  
Surrogate Marker ◽  
Dominant Negative ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

PPARG, a ligand-activated transcription factor plays a critical role in the regulation of blood pressure and vascular function. We hypothesized that smooth muscle cell (SMC) PPARG protects against hypertension (HT) and resistance vessel dysfunction. Transgenic mice expressing dominant negative PPARG (S-P467L) in SMC or non-transgenic controls (NT) were implanted with DOCA pellet and allowed ad libitum access to 0.15 M NaCl for 21 days in addition to regular chow and water. Blood pressure was monitored by telemetry and mesenteric arterial (MA) function was assessed by pressurized myograph. At baseline, 24-hour mean arterial pressure (MAP) was similar between NT and S-P467L mice, while the transgenic mice were tachycardic. DOCA-salt increased MAP to a much greater degree in S-P467L mice (Δ MAP; S-P467L: +34.2±6.0, NT: +13.3±5.7, p<0.05 vs NT). Heart rate was similarly decreased in both groups after DOCA-salt. Vasoconstriction to KCl, phenylephrine and endothelin-1 did not differ in MA from DOCA-salt treated NT and S-P467L, while the response to vasopressin was significantly reduced in S-P467L after DOCA-salt (% constriction at 10-8 M, S-P467L: 31.6±5.6, NT: 46.7±3.8, p<0.05 vs NT). Urinary copeptin, a surrogate marker for arginine vasopressin was similar in both groups regardless of treatment. Vasorelaxation to acetylcholine was slightly impaired in S-P467L MA compared to NT at baseline whereas this effect was further exaggerated after DOCA-salt (% relaxation at 10-5 M, S-P467L: 56.1±8.3, NT: 79.4±5.6, p<0.05 vs NT). Vascular morphology at luminal pressure of 75 mmHg showed a significant increase in wall thickness (S-P467L: 18.7±0.8, NT: 16.0±0.4, p<0.05 vs NT) and % media/lumen (S-P467L: 8.4±0.3, NT: 7.1±0.2, p<0.05 vs NT) in S-P467L MA after DOCA-salt. Expression of tissue inhibitor of metalloproteinases (TIMP)-4 and regulator of G-protein signaling (RGS)-5 transcript were 2- and 3.5-fold increased, respectively, in MA of NT with DOCA-salt compared to NT baseline. However, this induction was markedly blunted in S-P467L MA. We conclude that interference with PPARG function in SMC leads to altered gene expression crucial for normal vascular homeostasis, thereby sensitizing the mice to the effects of DOCA-salt induced HT and vascular dysfunction.

scholarly journals Direct regulation of blood pressure by smooth muscle cell mineralocorticoid receptors

2012 ◽  
Vol 18 (9) ◽  
pp. 1429-1433 ◽  
Author(s):  
Amy McCurley ◽  
Paulo W Pires ◽  
Shawn B Bender ◽  
Mark Aronovitz ◽  
Michelle J Zhao ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Mineralocorticoid Receptors ◽  
Regulation Of Blood Pressure ◽  
Direct Regulation

scholarly journals Low-intensity interval exercise training attenuates coronary vascular dysfunction and preserves Ca2+-sensitive K+ current in miniature swine with LV hypertrophy

2011 ◽  
Vol 301 (4) ◽  
pp. H1687-H1694 ◽  
Author(s):  
Craig A. Emter ◽  
Darla L. Tharp ◽  
Jan R. Ivey ◽  
Venkataseshu K. Ganjam ◽  
Douglas K. Bowles
Keyword(s):  
Smooth Muscle ◽  
Exercise Training ◽  
Smooth Muscle Cell ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Miniature Swine ◽  
Vascular Conductance ◽  
Coronary Smooth Muscle ◽  
Interval Exercise ◽  
Low Intensity

Coronary vascular dysfunction has been observed in several models of heart failure (HF). Recent evidence indicates that exercise training is beneficial for patients with HF, but the precise intensity and underlying mechanisms are unknown. Left ventricular (LV) hypertrophy can play a significant role in the development of HF; therefore, the purpose of this study was to assess the effects of low-intensity interval exercise training on coronary vascular function in sedentary (HF) and exercise trained (HF-TR) aortic-banded miniature swine displaying LV hypertrophy. Six months postsurgery, in vivo coronary vascular responses to endothelin-1 (ET-1) and adenosine were measured in the left anterior descending coronary artery. Baseline and maximal coronary vascular conductance were similar between all groups. ET-1-induced reductions in coronary vascular conductance ( P < 0.05) were greater in HF vs. sedentary control and HF-TR groups. Pretreatment with the ET type A (ETA) receptor blocker BQ-123 prevented ET-1 hypersensitivity in HF animals. Whole cell voltage clamp was used to characterize composite K+ currents ( IK+) in coronary smooth muscle cells. Raising internal Ca2+ from 200 to 500 nM increased Ca2+-sensitive K+ current in HF-TR and control, but not HF animals. In conclusion, an ETA-receptor-mediated hypersensitivity to ET-1, elevated resting LV wall tension, and decreased coronary smooth muscle cell Ca2+-sensitive IK+ was found in sedentary animals with LV hypertrophy. Low-intensity interval exercise training preserved normal coronary vascular function and smooth muscle cell Ca2+-sensitive IK+, illustrating a potential mechanism underlying coronary vascular dysfunction in a large-animal model of LV hypertrophy. Our results demonstrate the potential clinical impact of exercise on coronary vascular function in HF patients displaying pathological LV hypertrophy.

Vascular smooth muscle Gq signaling is involved in high blood pressure in both induced renal and genetic vascular smooth muscle-derived models of hypertension

2007 ◽  
Vol 293 (5) ◽  
pp. H3072-H3079 ◽  
Author(s):  
David M. Harris ◽  
Heather I. Cohn ◽  
Stéphanie Pesant ◽  
Rui-Hai Zhou ◽  
Andrea D. Eckhart
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Renal Artery ◽  
Renal Artery Stenosis ◽  
Antihypertensive Therapy ◽  
High Blood Pressure ◽  
Vascular Function ◽  
Artery Stenosis ◽  
Ang Ii

More than 30% of the US population has high blood pressure (BP), and less than a third of people treated for hypertension have it controlled. In addition, the etiology of most high BP is not known. Having a better understanding of the mechanisms underlying hypertension could potentially increase the effectiveness of treatment. Because Gq signaling mediates vasoconstriction and vascular function can cause BP abnormalities, we were interested in determining the role of vascular smooth muscle (VSM) Gq signaling in two divergent models of hypertension: a renovascular model of hypertension through renal artery stenosis and a genetic model of hypertension using mice with VSM-derived high BP. Inhibition of VSM Gq signaling attenuated BP increases induced by renal artery stenosis to a similar extent as losartan, an ANG II receptor blocker and current antihypertensive therapy. Inhibition of Gq signaling also attenuated high BP in our genetic VSM-derived hypertensive model. In contrast, BP remained elevated 25% following treatment with losartan, and prazosin, an α1-adrenergic receptor antagonist, only decreased BP by 35%. Inhibition of Gq signaling attenuated VSM reactivity to ANG II and resulted in a 2.4-fold rightward shift in EC50. We also determined that inhibition of Gq signaling was able to reverse VSM hypertrophy in the genetic VSM-derived hypertensive model. These results suggest that Gq signaling is an important signaling pathway in two divergent models of hypertension and, perhaps, optimization of antihypertensive therapy could occur with the identification of particular Gq-coupled receptors involved.

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