scholarly journals The control of Ca2+ influx and NFATc3 signaling in arterial smooth muscle during hypertension

2008 ◽  
Vol 105 (40) ◽  
pp. 15623-15628 ◽  
Author(s):  
Madeline Nieves-Cintrón ◽  
Gregory C. Amberg ◽  
Manuel F. Navedo ◽  
Jeffery D. Molkentin ◽  
Luis F. Santana
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Blood Pressure ◽  
Smooth Muscle ◽  
Vascular Dysfunction ◽  
Signaling Cascade ◽  
Myogenic Tone ◽  
Excitable Cells ◽  
Open Probability ◽  
Induced Hypertension

Many excitable cells express L-type Ca2+ channels (LTCCs), which participate in physiological and pathophysiological processes ranging from memory, secretion, and contraction to epilepsy, heart failure, and hypertension. Clusters of LTCCs can operate in a PKCα-dependent, high open probability mode that generates sites of sustained Ca2+ influx called “persistent Ca2+ sparklets.” Although increased LTCC activity is necessary for the development of vascular dysfunction during hypertension, the mechanisms leading to increased LTCC function are unclear. Here, we tested the hypothesis that increased PKCα and persistent Ca2+ sparklet activity contributes to arterial dysfunction during hypertension. We found that PKCα and persistent Ca2+ sparklet activity is indeed increased in arterial myocytes during hypertension. Furthermore, in human arterial myocytes, PKCα-dependent persistent Ca2+ sparklets activated the prohypertensive calcineurin/NFATc3 signaling cascade. These events culminated in three hallmark signs of hypertension-associated vascular dysfunction: increased Ca2+ entry, elevated arterial [Ca2+]i, and enhanced myogenic tone. Consistent with these observations, we show that PKCα ablation is protective against the development of angiotensin II-induced hypertension. These data support a model in which persistent Ca2+ sparklets, PKCα, and calcineurin form a subcellular signaling triad controlling NFATc3-dependent gene expression, arterial function, and blood pressure. Because of the ubiquity of these proteins, this model may represent a general signaling pathway controlling gene expression and cellular function.

scholarly journals Role of myosin light chain kinase in regulation of basal blood pressure and maintenance of salt-induced hypertension

2011 ◽  
Vol 301 (2) ◽  
pp. H584-H591 ◽  
Author(s):  
Wei-Qi He ◽  
Yan-Ning Qiao ◽  
Cheng-Hai Zhang ◽  
Ya-Jing Peng ◽  
Chen Chen ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Light Chain ◽  
Myosin Light Chain Kinase ◽  
Myosin Light Chain ◽  
Vascular Tone ◽  
Induced Hypertension ◽  
Basal Blood Pressure ◽  
Muscle Myosin

Vascular tone, an important determinant of systemic vascular resistance and thus blood pressure, is affected by vascular smooth muscle (VSM) contraction. Key signaling pathways for VSM contraction converge on phosphorylation of the regulatory light chain (RLC) of smooth muscle myosin. This phosphorylation is mediated by Ca2+/calmodulin-dependent myosin light chain kinase (MLCK) but Ca2+-independent kinases may also contribute, particularly in sustained contractions. Signaling through MLCK has been indirectly implicated in maintenance of basal blood pressure, whereas signaling through RhoA has been implicated in salt-induced hypertension. In this report, we analyzed mice with smooth muscle-specific knockout of MLCK. Mesenteric artery segments isolated from smooth muscle-specific MLCK knockout mice (MLCKSMKO) had a significantly reduced contractile response to KCl and vasoconstrictors. The kinase knockout also markedly reduced RLC phosphorylation and developed force. We suggest that MLCK and its phosphorylation of RLC are required for tonic VSM contraction. MLCKSMKO mice exhibit significantly lower basal blood pressure and weaker responses to vasopressors. The elevated blood pressure in salt-induced hypertension is reduced below normotensive levels after MLCK attenuation. These results suggest that MLCK is necessary for both physiological and pathological blood pressure. MLCKSMKO mice may be a useful model of vascular failure and hypotension.

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.

Abstract 212: Hydrogen Peroxide Acutely Stimulates Cardiogenic Gene Expression in Cardiac Progenitor Cells

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Karl D Pendergrass ◽  
Michael E Davis
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Hydrogen Peroxide ◽  
Smooth Muscle ◽  
Progenitor Cells ◽  
Matched Control ◽  
Cardiac Progenitor Cells ◽  
H2o2 Treatment ◽  
Apoptotic Effect ◽  
H2o2 Pretreatment

Following acute myocardial infarction, billions of myocytes are lost to cell death. The damage is regional and lost cells are replaced with a collagen scar. One potential therapy to delay or prevent progression into heart failure is regeneration of the damaged myocardium through cell therapy with cardiac progenitor cells (CPC). Reactive oxygen species, specifically hydrogen peroxide, elicit varying responses from different stem/progenitor cells. In the present studies, we sought to determine the effect of acute H2O2 treatment on CPC survival and differentiation. CPCs were isolated and cultured with leukemia inhibitory factor (LIF) to retain their stem-like qualities. CPCs were allowed to differentiate in the absence of LIF for up to 5 days + H2O2. H2O2 (100μM) significantly increased expression of the smooth muscle marker, alpha smooth muscle actin (αSM) by Day 2 as compared to time-matched controls (Ctl: 1.8+1.3 vs 100 μM: 8.5+1.1; p<0.001; N=3). We also observed a trend for an increase in smooth muscle 22 alpha (SM 22α) gene expression by Day 2. Interestingly, by Day 5 the stimulatory effect of 100 μM H2O2 treatment on α SM and SM 22α was reversed and significantly decreased compared to Day 2 (D5: α SM: 0.43+0.05, SM 22α: 0.41+0.2 vs. D2: SM 22α: 10.58+2.3; p<0.01; N=3-4). Evaluation of the endothelial marker VEGFR-2 (Flk-1) showed a trend for an increase in gene expression by Day 2 following 100 μM H2O2 treatment compared to the time-matched control. We also observed an anti-apoptotic effect on CPCs following serum removal, in which 2 days of 100μM H2O2 pretreatment lead to approximately a 55% decrease in cell death compared to untreated CPCs (Ctl: 19.1+2.4 vs 100 μM: 10.5+1.7; p<0.05; N=3-4). The protective effect of the H2O2 pretreatment could be attributed to an increase in anti-oxidative enzymatic capacity in CPCs. There was a trend for an increase in catalase gene expression. In conclusion, our results showed that acute H2O2 preconditioning exerted a stimulatory effect on smooth muscle gene expression and an anti-apoptotic effect compared to time-matched Control CPCs. Furthermore, acute H2O2 preconditioning may aid in directing CPC differentiation towards a vascular phenotype and angiogenesis in the infarcted myocardium, which may prevent or delay heart failure.

scholarly journals Interleukin-9 Deletion Relieves Vascular Dysfunction and Decreases Blood Pressure via the STAT3 Pathway in Angiotensin II-Treated Mice

2020 ◽  
Vol 2020 ◽  
pp. 1-12 ◽  
Author(s):  
Yunzhao Yang ◽  
Shaoqun Tang ◽  
Chunchun Zhai ◽  
Xin Zeng ◽  
Qingjian Liu ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Inflammatory Response ◽  
Vascular Dysfunction ◽  
Control Group ◽  
Dependent Manner ◽  
Ang Ii ◽  
Stat3 Pathway

Background. Multiple interleukin (IL) family members were reported to be closely related to hypertension. We aimed to investigate whether IL-9 affects angiotensin II- (Ang II-) induced hypertension in mice. Methods. Mice were treated with Ang II, and IL-9 expression was determined. In addition, effects of IL-9 knockout (KO) on blood pressure were observed in Ang II-infused mice. To determine whether the effects of IL-9 on blood pressure was mediated by the signal transducer and activator of the transcription 3 (STAT3) pathway, Ang II-treated mice were given S31-201. Furthermore, circulating IL-9 levels in patients with hypertension were measured. Results. Ang II treatment increased serum and aortic IL-9 expression in a dose-dependent manner; IL-9 levels were the highest in the second week and continued to remain high into the fourth week after the treatment. IL-9 KO downregulated proinflammatory cytokine expression, whereas it upregulated anti-inflammatory cytokine levels, relieved vascular dysfunction, and decreased blood pressure in Ang II-infused mice. IL-9 also reduced smooth muscle 22α (SM22α) expression and increased osteopontin (OPN) levels both in mice and in vitro. The effects of IL-9 KO on blood pressure and inflammatory response were significantly reduced by S31-201 treatment. Circulating IL-9 levels were significantly increased in patients with the hypertension group than in the control group, and elevated IL-9 levels positively correlated with both systolic blood pressure and diastolic blood pressure in patients with hypertension. Conclusions. IL-9 KO alleviates inflammatory response, prevents phenotypic transformation of smooth muscle, reduces vascular dysfunction, and lowers blood pressure via the STAT3 pathway in Ang II-infused mice. IL-9 might be a novel target for the treatment and prevention of clinical hypertension.

scholarly journals The mitochondria mediate the induction of NOX1 gene expression by aldosterone in an ATF-1-dependent manner

2011 ◽  
Vol 16 (2) ◽  
Author(s):  
Yanping Fu ◽  
Gang Shi ◽  
Yong Wu ◽  
Yasuyuki Kawai ◽  
Qing Tian ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Transcription Factor ◽  
Smooth Muscle ◽  
Complex I ◽  
Mitochondrial Respiratory Chain ◽  
Dependent Manner ◽  
Over Expression ◽  
Diphenylene Iodonium ◽  
Activating Transcription Factor

AbstractHigh aldosterone (Ald) levels can induce hypertrophy of vascular smooth muscle cells (VSMCs), which carries high risks of heart failure. A previous study showed that Ald induces hypertrophy of VSMCs by up-regulating NOX1, a catalytic subunit of NADPH oxidase that produces superoxides. However, the precise mechanism remains unknown. Diphenylene iodonium (DPI) is known as an inhibitor of complex I in the mitochondrial respiratory chain, and it was also found to almost completely suppress the induction of NOX1 mRNA and the phosphorylation of activating transcription factor (ATF-1) by PGF2α or PDGF in a rat VSMC cell line. In this study, we found that the Ald-induced phosphorylation of ATF-1 and NOX1 expression was significantly suppressed by DPI. Silencing of ATF-1 gene expression attenuated the induction of NOX1 mRNA expression, and over-expression of ATF-1 restored Ald-induced NOX1 expression. On the basis of this data, we show that the mitochondria mediate aldosterone-induced NOX1 gene expression in an ATF-1-dependent manner.

scholarly journals Vascular Dysfunction Predicts Future Deterioration of Left Ventricular Ejection Fraction in Patients with Heart Failure with Mildly Reduced Ejection Fraction

2021 ◽  
Vol 10 (24) ◽  
pp. 5980
Author(s):  
Shinji Kishimoto ◽  
Tatsuya Maruhashi ◽  
Masato Kajikawa ◽  
Takahiro Harada ◽  
Takayuki Yamaji ◽  
...  
Keyword(s):  
Heart Failure ◽  
Smooth Muscle ◽  
Ejection Fraction ◽  
Vascular Smooth Muscle ◽  
Endothelial Function ◽  
Muscle Function ◽  
Vascular Dysfunction ◽  
Left Ventricular Ejection ◽  
Reduced Ejection Fraction ◽  
Smooth Muscle Function

The purpose of this study was to evaluate whether heart failure with mildly reduced ejection fraction (HFmrEF) is associated with vascular dysfunction and whether vascular function predicts future deterioration of LVEF in patients with HFmrEF. We evaluated endothelial function assessed by flow-mediated vasodilation (FMD) and vascular smooth muscle function assessed by nitroglycerine-induced vasodilation (NID) in 69 patients with HFmrEF and 426 patients without HF and evaluated the future deterioration of LVEF, defined as a decrease in LVEF to <40%, in 39 patients with HFmrEF for up to 3 years. Both FMD and NID were significantly lower in patients with HFmrEF than in patients without HF. We categorized patients into two groups based on low tertiles of NID: a low group (NID of <7.0%) and an intermediate and high group (NID of ≥7.0%). There were significant differences between the Kaplan–Meier curves for the deterioration of LVEF in the two groups (p < 0.01). Multivariate Cox proportional hazard analysis revealed that NID of <7.0% was an independent predictor of future deterioration of LVEF in patients with HFmrEF. Both endothelial function and vascular smooth muscle function are impaired in patients with HFmrEF compared with those in patients without HF. In addition, low NID of <7.0% predicts future deterioration of LVEF.

Abstract 352: Anti-aging Gene Klotho Deficiency Causes Hypertension and Vascular Dysfunction via Upregulation of Mammalian Target of Rapamycin (mTOR)

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Ying Song ◽  
Zhongjie Sun
Keyword(s):  
Blood Pressure ◽  
Nadph Oxidase ◽  
Oxidase Activity ◽  
Aging Process ◽  
Vascular Dysfunction ◽  
Mammalian Target Of Rapamycin ◽  
Genetic Mutation ◽  
Oxidase Inhibitor ◽  
Nadph Oxidase Activity ◽  
Induced Hypertension

Klotho is a recently discovered anti-aging gene. Genetic mutation of klotho expedites the aging process and shortens the lifespan while overexpression of klotho slows down the aging process and extends the lifespan by 20%. Interestingly, blood pressure (BP) was elevated significantly and vasodilatory responses to acetylcholine and sodium nitroprusside were impaired in klotho heterozygeous (+/-) mice, suggesting that klotho deficiency causes hypertension and vascular dysfunction. It is noted that klotho deficiency is associated with upregulation of mTOR expression and NADPH oxidase activity and downregulation of Mn-SOD expression in aortas and kidneys. Inhibition of mTOR by rapamycin abolished the upregulation of NADPH oxidase activity and O 2 - production and the downregulation of Mn-SOD expression and decreased BP to the control levels. Inhibition of mTOR also abolished vascular endothelial dysfunction and macrophage infiltration in kidneys in klotho (+/-) mice. The upregulation of NADPH oxidase activity and downregulation of Mn-SOD may be involved in klotho deficiency-induced hypertension which can be decreased significantly by apocynin (NADPH oxidase inhibitor) or Tempol (O 2 - scavenger). These results demonstrate, for the first time, that klotho is essential in the maintenance of normal blood pressure. Klotho deficiency-induced hypertension and vascular dysfunction are mediated by upregulation of mTOR. This study also reveals a previously unidentified role of mTOR in the regulation of NADPH oxidase and MnSOD. (Supported by HL105302 and HL102074).

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