Effect of CCL5 on dimethylarginine dimethylaminohydrolase-1 production in vascular smooth muscle cells from spontaneously hypertensive rats

Kim, Hye Young; Kim, Jung Hae; Kim, Hee Sun

doi:10.1016/j.cyto.2013.06.316

Cited by 16 publications

(20 citation statements)

References 22 publications

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“…5,11,13 The tissue distribution of DDAH1 has been widely studied, with expression found in numerous tissues and cell types. 12,[18][19][20][21][22] However, more recently, it has been suggested that the vast majority of DDAH1 expression is confined to endothelial cells 17 and that this is the major site of ADMA metabolism.…”

Section: Discussionmentioning

confidence: 99%

“…These observations seem at odds with previous reports that have identified DDAH1 expression in a wide range of nonendothelial cell types, including vascular smooth muscle, renal, and neuronal cells. [18][19][20][21][22][23][24] To resolve this apparent discrepancy, we have independently generated an endothelium-specific DDAH1 −/− mouse. Using this model, we demonstrate endothelium-restricted expression of Cre activity that entirely removes DDAH1 protein in primary isolated endothelial cells.…”

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confidence: 99%

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Endothelial Dimethylarginine Dimethylaminohydrolase 1 Is an Important Regulator of Angiogenesis but Does Not Regulate Vascular Reactivity or Hemodynamic Homeostasis

et al. 2015

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Clinical Perspective on p 2225In healthy individuals, plasma ADMA concentrations are maintained at ≈0.5μmol/L through a combination of enzymatic breakdown and renal excretion that account for ≈80% and ≈20% of clearance, respectively.10 Asymmetrical methylarginines are metabolized by the action of dimethylarginine Background-Asymmetrical dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthesis and a risk factor for cardiovascular disease. Dimethylarginine dimethylaminohydrolase (DDAH) enzymes are responsible for ADMA breakdown. It has been reported that endothelial DDAH1 accounts for the majority of ADMA metabolism. However, we and others have shown strong DDAH1 expression in a range of nonendothelial cell types, suggesting that the endothelium is not the only site of metabolism. We have developed a new endothelium-specific DDAH1 knockout mouse (DDAH1) to investigate the significance of endothelial ADMA in cardiovascular homeostasis. Methods and Results-DDAH1 deletion in the DDAH1En−/− mouse was mediated by Tie-2 driven Cre expression. DDAH1 deletion was confirmed through immunocytochemistry, whereas Western blotting showed that DDAH1 remained in the kidney and liver, confirming expression in nonendothelial cells. Plasma ADMA was unchanged in DDAH1En−/− mice, and cultured aortas released amounts of ADMA to similar to controls. Consistent with these observations, vasoreactivity ex vivo and hemodynamics in vivo were unaltered in DDAH1 En−/− mice. In contrast, we observed significantly impaired angiogenic responses both ex vivo and in vivo. Conclusions-We demonstrate that endothelial DDAH1 is not a critical determinant of plasma ADMA, vascular reactivity, or hemodynamic homeostasis. DDAH1 is widely expressed in a range of vascular and nonvascular cell types; therefore, the additive effect of DDAH1 expression in multiple organ systems determines plasma ADMA concentrations. Endothelial deletion of DDAH1 profoundly impairs the angiogenic capacity of endothelial cells, indicating that intracellular ADMA is a critical determinant of endothelial cell response.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Endothelial Dimethylarginine Dimethylaminohydrolase 1 Is an Important Regulator of Angiogenesis but Does Not Regulate Vascular Reactivity or Hemodynamic Homeostasis

et al. 2015

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“…and mediate the inhibitory effect of CCL5 on Ang II-induced 12-LO and ET-1 expression in SHR VSMCs (14,15). In this study, elevated AMPK expression was observed in SHRi thoracic aortas and VSMCs (Fig.…”

Section: Ampk and Ddah Activities Are Up-regulated By Ccl5mentioning

confidence: 60%

“…Therefore, CCL5 plays diverse roles in accordance with inflammatory and disease states. (14,15). Therefore, although CCL5 is known as an inflammatory mediator in the pathogenesis of various diseases, it plays an down-regulatory role in Ang II-induced hypertensive mediators expression, which is in contrast to the enhanced roles of proinflammatory chemokines in hypertension development and maintenance (3,4,16,17).…”

Section: Introductionmentioning

confidence: 90%

CCL5 Inhibits Elevation of Blood Pressure and Expression of Hypertensive Mediators in Developing Hypertension State Spontaneously Hypertensive Rats

Kim

Choi

et al. 2015

J Bacteriol Virol

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CCL5, a proinflammatory chemokine, has been shown to attenuate angiotensin (Ang) II-induced expression of hypertensive mediators as well as Ang II-induced inhibition of anti-hypertensive mediator expression in vascular smooth muscle cells (VSMCs) of spontaneously hypertensive rats (SHR). In the present study, functional roles of CCL5 on hypertension were examined in developing hypertension state SHR (DHSHR). DHSHR at an age of 8 weeks were injected CCL5 (1.5 μg/kg) subcutaneously twice a day for 3 weeks (SHRi, n=5). Control groups consisted of normal age-matched saline-treated SHR (SHRc, n=5) and normotensive Wistar-Kyoto rats (WKY, n=5). Effect of CCL5 on blood pressure was measured before treatment, weekly during treatment, and 1 day after the final injection. After injecting for 3 weeks, effects of CCL5 on expression of hypertensive mediators were examined in thoracic aorta tissues and VSMCs. Blood pressure in SHRi was maintained without any elevation during the treatment period, whereas blood pressure in SHRc progressively increased with age. Expression of Ang II subtype I receptor was reduced in SHRi thoracic aorta tissues and VSMCs compared to those in SHRc. In addition, expression levels of hypertensive mediators were significantly reduced in SHRi thoracic aorta tissues and VSMCs compared to those in SHRc. In contrast, AMP-activated protein kinase (AMPK) activity and interleukin-10 (IL-10) expression were elevated in SHRi thoracic aorta tissues and VSMCs compared to levels in SHRc. These results suggest that reduction of hypertensive mediators and elevation of antihypertensive mediators by CCL5 treatment promotes maintenance of blood pressure in DHSHR.

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“…In addition, the expression of IL-10-induced dimethylarginine dimethylaminohydrolase, a down-regulator of hypertension, has been mediated by the AT2 R pathway [27]. Namely, an association between AT2 R pathway and anti-hypertensive actions of IL-10 and CCL5 in SHR VSMCs has been determined [26][27][28]. However, the functional roles of AT2 R remain controversial.…”

Section: Discussionmentioning

confidence: 99%

Sulfatase 1 mediates the inhibitory effect of angiotensin II type 2 receptor inhibitor on angiotensin II-induced hypertensive mediator expression and proliferation in vascular smooth muscle cells from spontaneously hypertensive rats

Kim

2017

Yeungnam Univ J Med

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Background: Extracellular sulfatases (Sulfs), sulfatase 1 (Sulf1) and sulfatase 2 (Sulf2), play a pivotal role in cell signaling by remodeling the 6-O-sulfation of heparan sulfate proteoglycans on the cell surface. The present study examined the effects of Sulfs on angiotensin II (Ang II)-induced hypertensive mediator expression and vascular smooth muscle cells (VSMCs) proliferation in spontaneously hypertensive rats (SHR). Methods: Ang II receptors, 12-lipoxygenase (12-LO), and endothelin-1 (ET-1) messenger RNA (mRNA) expressions in SHR VSMCs were analyzed by real-time polymerase chain reaction and Western blotting. VSMCs proliferation was determined by [ 3 H]-thymidine incorporation. Results: Basal Sulfs mRNAs expression and enzyme activity were elevated in SHR VSMCs. However, Sulfs had no effect on the basal or Ang II-induced 12-LO and ET-1 mRNA expression in SHR VSMCs. The inhibition of Ang II-induced 12-LO and ET-1 expression by blockade of the Ang II type 2 receptor (AT2 R) pathway was not observed in Sulf1 siRNA-transfected SHR VSMCs. However, Sulf2 did not affect the action of AT2 R inhibitor on Ang II-induced 12-LO and ET-1 expression in SHR VSMCs. The down-regulation of Sulf1 induced a reduction of AT2 R mRNA expression in SHR VSMCs. In addition, the inhibition of Ang II-induced VSMCs proliferation by blockade of the AT2 R pathway was mediated by Sulf1 in SHR VSMCs. Conclusion: These findings suggest that extracellular sulfatase Sulf1 plays a modulatory role in the AT2 R pathway that leads to an Ang II-induced hypertensive effects in SHR VSMCs.

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Effect of CCL5 on dimethylarginine dimethylaminohydrolase-1 production in vascular smooth muscle cells from spontaneously hypertensive rats

Cited by 16 publications

References 22 publications

Endothelial Dimethylarginine Dimethylaminohydrolase 1 Is an Important Regulator of Angiogenesis but Does Not Regulate Vascular Reactivity or Hemodynamic Homeostasis

Endothelial Dimethylarginine Dimethylaminohydrolase 1 Is an Important Regulator of Angiogenesis but Does Not Regulate Vascular Reactivity or Hemodynamic Homeostasis

CCL5 Inhibits Elevation of Blood Pressure and Expression of Hypertensive Mediators in Developing Hypertension State Spontaneously Hypertensive Rats

Sulfatase 1 mediates the inhibitory effect of angiotensin II type 2 receptor inhibitor on angiotensin II-induced hypertensive mediator expression and proliferation in vascular smooth muscle cells from spontaneously hypertensive rats

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