scholarly journals Vascular Stiffening Mediated by Rho‐Associated Coiled‐Coil Containing Kinase Isoforms

2021 ◽  
Author(s):  
Yuxin Li ◽  
Haw‐Chih Tai ◽  
Nikola Sladojevic ◽  
Hyung‐Hwan Kim ◽  
James K. Liao
Keyword(s):  
Angiotensin Ii ◽  
Methyl Ester ◽  
Vascular Remodeling ◽  
Transforming Growth Factor ◽  
Coiled Coil ◽  
Therapeutic Benefits ◽  
Age Related ◽  
Vascular Stiffening ◽  
Aortic Stiffening

Background The pathogenesis of vascular stiffening and hypertension is marked by non‐compliance of vessel wall because of deposition of collagen fibers, loss of elastin fibers, and increased vascular thickening. Rho/Rho‐associated coiled‐coil containing kinases 1 and 2 (ROCK1 and ROCK2) have been shown to regulate cellular contraction and vascular remodeling. However, the role of ROCK isoforms in mediating pathogenesis of vascular stiffening and hypertension is not known. Methods and Results Hemizygous Rock mice ( Rock1 +/− and Rock2 +/− ) were used to determine the role of ROCK1 and ROCK2 in age‐related vascular dysfunction. Both ROCK activity and aortic stiffness increased to a greater extent with age in wild‐type mice compared with that of Rock1 +/− and Rock2 +/− mice. As a model for age‐related vascular stiffening, we administered angiotensin II (500 ng/kg per minute) combined with nitric oxide synthase inhibitor, L‐N ω ‐nitroarginine methyl ester (0.5 g/L) for 4 weeks to 12‐week‐old male Rock1 +/− and Rock2 +/− mice. Similar to advancing age, angiotensin II/L‐N ω ‐nitroarginine methyl ester caused increased blood pressure, aortic stiffening, and vascular remodeling, which were attenuated in Rock2 +/− , and to a lesser extent, Rock1 +/− mice. The reduction of aortic stiffening in Rock2 +/− mice was accompanied by decreased collagen deposition, relatively preserved elastin content, and less aortic wall hypertrophy. Indeed, the upregulation of collagen I by transforming growth factor‐β1 or angiotensin II was greatly attenuated in Rock2 −/− mouse embryonic fibroblasts. Conclusions These findings indicate that ROCK1 and ROCK2 mediate both age‐related and pharmacologically induced aortic stiffening, and suggest that inhibition of ROCK2, and to a lesser extent ROCK1, may have therapeutic benefits in preventing age‐related vascular stiffening.

Abstract 070: AntagomiR-762 Prevents Angiotensin II Induced Aortic Fibrosis and Stiffening

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Kim Ramil C Montaniel ◽  
Jing Wu ◽  
Matthew R Bersi ◽  
Liang Xiao ◽  
Hana A Itani ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Organ Damage ◽  
Matrix Proteins ◽  
Locked Nucleic Acid ◽  
Ang Ii ◽  
End Organ Damage ◽  
Acid Inhibitor ◽  
Vascular Stiffening ◽  
Aortic Stiffening

We and others have shown that hypertension (HTN) is associated with a striking deposition of collagen in the vascular adventitia. This causes vascular stiffening, which increases pulse wave velocity and contributes to end-organ damage. Through a screen of vascular microRNAs (miRNAs), we found that miR-762 is the most upregulated miRNA in mice with angiotensin II (Ang II)-induced HTN. qRT-PCR confirmed that miR-762 is upregulated 6.35±1.22 (p=0.03) fold in aortas of Ang II-infused mice compared with controls. This was a direct effect of Ang II, as miR-762 upregulation was not eliminated by lowering blood pressure with hydralazine and hydrochlorothiazide and was increased only 2-fold in DOCA salt HTN. To study the role of miR-762 in HTN, we administered a locked nucleic acid inhibitor of miR-762 (antagomiR-762). AntagomiR-762 administration did not alter the hypertensive response to Ang II, yet it normalized stress-strain relationships and aortic energy storage that occurs in systole (Table). Further studies showed that antagomiR-762 dramatically affected vascular matrix proteins, reducing mRNA for several collagens and fibronectin and dramatically upregulating collagenases MMP1a, 8 and 13 (Table). Thus, miR-762 has a major role in modulating vascular stiffening and its inhibition dramatically inhibits pathological fibrosis, enhances matrix degradation and normalizes aortic stiffness. AntagomiR-762 might represent a new approach to prevent aortic stiffening and its consequent end-organ damage.

scholarly journals The Nutraceutical N-Palmitoylethanolamide (PEA) Reveals Widespread Molecular Effects Unmasking New Therapeutic Targets in Murine Varicocele

Nutrients ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 734
Author(s):  
Pietro Antonuccio ◽  
Herbert Ryan Marini ◽  
Antonio Micali ◽  
Carmelo Romeo ◽  
Roberta Granese ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Therapeutic Targets ◽  
Sham Operation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pyrin Domain ◽  
Age Related ◽  
Extracellular Signal ◽  
Morphometric Assessment

Varicocele is an age-related disease with no current medical treatments positively impacting infertility. Toll-like receptor 4 (TLR4) expression is present in normal testis with an involvement in the immunological reactions. The role of peroxisome proliferator-activated receptor-α (PPAR-α), a nuclear receptor, in fertility is still unclear. N-Palmitoylethanolamide (PEA), an emerging nutraceutical compound present in plants and animal foods, is an endogenous PPAR-α agonist with well-demonstrated anti-inflammatory and analgesics characteristics. In this model of mice varicocele, PPAR-α and TLR4 receptors’ roles were investigated through the administration of ultra-micronized PEA (PEA-um). Male wild-type (WT), PPAR-α knockout (KO), and TLR4 KO mice were used. A group underwent sham operation and administration of vehicle or PEA-um (10 mg/kg i.p.) for 21 days. Another group (WT, PPAR-α KO, and TLR4 KO) underwent surgical varicocele and was treated with vehicle or PEA-um (10 mg/kg i.p.) for 21 days. At the end of treatments, all animals were euthanized. Both operated and contralateral testes were processed for histological and morphometric assessment, for PPAR-α, TLR4, occludin, and claudin-11 immunohistochemistry and for PPAR-α, TLR4, transforming growth factor-beta3 (TGF-β3), phospho-extracellular signal-Regulated-Kinase (p-ERK) 1/2, and nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) Western blot analysis. Collectively, our data showed that administration of PEA-um revealed a key role of PPAR-α and TLR4 in varicocele pathophysiology, unmasking new nutraceutical therapeutic targets for future varicocele research and supporting surgical management of male infertility.

scholarly journals The Potential Association between the Risk of Post-Surgical Adhesion and the Activated Local Angiotensin II Type 1 Receptors: Need for Novel Treatment Strategies

2021 ◽  
pp. 1-8
Author(s):  
Mahmood Tavakkoli ◽  
Saeed Aali ◽  
Borzoo Khaledifar ◽  
Gordon A. Ferns ◽  
Majid Khazaei ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Therapeutic Potential ◽  
Angiotensin Receptor Blockers ◽  
Surgical Techniques ◽  
Treatment Strategies ◽  
Transforming Growth Factor Β

<b><i>Background:</i></b> Post-surgical adhesion bands (PSABs) are a common complication after abdominal or pelvic surgeries for different reasons like cancer treatment. Despite improvements in surgical techniques and the administration of drugs or the use of physical barriers, there has only been limited improvement in the frequency of postoperative adhesions. Complications of PSAB are pain, infertility, intestinal obstruction, and increased mortality. The most important molecular mechanisms for the development of PSAB are inflammatory response, oxidative stress, and overexpression of pro-fibrotic molecules such as transforming growth factor β. However, questions remain about the pathogenesis of this problem, for example, the causes for individual differences or why certain tissue sites are more prone to post-surgical adhesions. <b><i>Summary:</i></b> Addressing the pathological causes of PSAB, the potential role of local angiotensin II/angiotensin II type 1 receptors (AngII/AT1R), may help to prevent this problem. <b><i>Key Message:</i></b> The objective of this article was to explore the role of the AngII/AT1R axis potential to induce PSAB and the therapeutic potential of angiotensin receptor blockers in the prevention and treatment of PSAB.

Abstract 65: Restoration of Growth Differentiation Factor 11 Protects Against Stroke in Mice

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Anjali Chauhan ◽  
Jacob Hudobenko ◽  
Anthony Patrizz ◽  
Louise D McCullough
Keyword(s):  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
The Elderly ◽  
Vehicle Group ◽  
Peripheral Tissues ◽  
Delayed Treatment ◽  
Aged Mice ◽  
Infarct Area ◽  
Age Related

Introduction: GDF 11 is a member of the transforming growth factor β superfamily. Loss of GDF11 occurs with aging and declining levels correlate with several detrimental age-associated phenotypes in both peripheral tissues and brain. Restoration of GDF11 enhances neurogenesis and cognitive function in aged mice. Brain expression of GDF11 has not been investigated after stroke. Stroke differentially affects the elderly. In this work we examined the role of GDF11 in aging, stroke and its potential utility as a neuroprotective agent. Methods: Male C57/BL6NCrl young (2-3 months) and aged (19-21) mice were used. Brain GDF11 expression was evaluated in young and aged mice by western blot. Focal ischemia was induced with a transient middle cerebral artery occlusion (MCAO). Mice were randomly assigned into two groups and were subjected to 90 min MCAO. Group 1 received vehicle (phosphate buffered saline) and group 2 was administered rGDF11 (100 ug/kg., ip) at the onset of ischemia. In additional experiments, the efficacy of delayed treatment (3 h after ischemia) with rGDF11 was tested. These mice were subjected to a 60 min MCAO. Mice were euthanized after 24 hours and 7 days respectively and brains were harvested to estimate infarct area. Results: A significant decrease in brain GDF11 levels was observed in aged mice as compared to young (p<0.05). Additionally, a significant decline in brain GDF11 expression was observed after stroke at 24 hours vs. sham groups (p<0.05). A significant decrease in cortical and hemispheric infarct area was observed in the rGDF11 group (cortical 48.73±1.05; hemisphere 49.68±3.58) as compared to vehicle group (60.54±4.88; 61.35±6.03), when GDF was administered at the time of ischemia. Delayed treatment with rGDF11 also reduced infarct at 7 days. Conclusions: Brain GDF11 levels decline with age and after stroke. Supplementation with rGDF11 ameliorates stroke induced injury in young mice at 24h and 7 days. These finding suggest potential role of GDF11 in age and stroke. Restoration of age-related loss of GDF may be a viable therapy for stroke.

scholarly journals The role of adventitial resident Sca‐1 + progenitor cells in angiotensin II‐induced aortic stiffening (867.3)

2014 ◽  
Vol 28 (S1) ◽  
Author(s):  
Jing Wu ◽  
Virginia Hoglund ◽  
Xiu Dong ◽  
Wei Chen ◽  
Mark Majesky ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Progenitor Cells ◽  
Aortic Stiffening

scholarly journals Angiotensin-Converting Enzyme 2 as a Possible Correlation between COVID-19 and Periodontal Disease

2020 ◽  
Vol 10 (18) ◽  
pp. 6224 ◽  
Author(s):  
Leonardo Mancini ◽  
Vincenzo Quinzi ◽  
Stefano Mummolo ◽  
Giuseppe Marzo ◽  
Enrico Marchetti
Keyword(s):  
Angiotensin Ii ◽  
Inflammatory Response ◽  
Angiotensin Converting Enzyme ◽  
Transforming Growth Factor ◽  
Tissue Injury ◽  
Interleukin 2 ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Cell Functions

SARS-CoV-2 propagation in the world has led to rapid growth and an acceleration in the discoveries and publications of various interests. The main focus of a consistent number of studies has been the role of angiotensin-converting enzyme 2 (ACE2) in binding the virus and its role in expression of the inflammatory response after transmission. ACE2 is an enzyme involved in the renin–angiotensin system (RAS), whose key role is to regulate and counter angiotensin-converting enzyme (ACE), reducing the amount of angiotensin II and increasing angiotensin 1–7 (Ang1–7), making it a promising drug target for treating cardiovascular diseases. The classical RAS axis, formed by ACE, angiotensin II (Ang II), and angiotensin receptor type 1 (AT1), activates several cell functions and molecular signalling pathways related to tissue injury and inflammation. In contrast, the RAS axis composed of ACE2, Ang1–7, and Mas receptor (MasR) exerts the opposite effect concerning the inflammatory response and tissue fibrosis. Recent studies have shown the presence of the RAS system in periodontal sites where osteoblasts, fibroblasts, and osteoclasts are involved in bone remodelling, suggesting that the role of ACE2 might have a fundamental function in the under- or overexpression of cytokines such as interleukin-6 (IL-6), interleukin-7 (IL-7), tumour necrosis factor alpha (TNF-α), interleukin-2 (IL-2), interleukin-1 beta (IL-1β), monocyte chemoattractant protein-1 (MCP-1), and transforming growth factor-beta (TGF-β), associated with a periodontal disorder, mainly during coinfection with SARS-CoV-2, where ACE2 is underexpressed and cannot form the ACE2–Ang1–7–MasR axis. This renders the patient unresponsive to an inflammatory process, facilitating periodontal loss.

scholarly journals Angiotensin II‐Induced Cardiac Vascular Remodeling: Role of Oxidative Stress

2007 ◽  
Vol 21 (6) ◽  
Author(s):  
Wenyuan Zhao ◽  
Dan Zhao ◽  
Yuanjian Chen ◽  
youde Jiang ◽  
Yao Sun
Keyword(s):  
Oxidative Stress ◽  
Angiotensin Ii ◽  
Vascular Remodeling

Role of estrogen in the management of COVID – 19 in females

2020 ◽  
Vol 10 (3) ◽  
pp. 67-70
Author(s):  
Keerthi Chadam Venkatesulu ◽  
Shaik Habeeb Jan ◽  
Harika Sree Gaddam
Keyword(s):  
Health Care Systems ◽  
Treatment Options ◽  
Adverse Outcomes ◽  
Older Individuals ◽  
Therapeutic Benefits ◽  
Age Related ◽  
Disease Condition ◽  
Care Systems ◽  
The Difference

With the increase, the spread of COVID-19 its effect can be seen on health care systems seek innovative treatment ways as the need of the hour. The suspected leading cause of COVID-19 is due to the response to inflammations and the cytokine storm, which majorly damages the lung tissue. The difference in response to the vaccine can be seen due to different sex. Moreover, age-related decrease in sex steroid hormones like Estrogen as well as testosterone can promote pro-inflammatory raise in older individuals which in turn increases the risk of COVID-19 related adverse outcomes. Such sex hormones have the capacity of mitigating inflammatory response and can also provide promising therapeutic benefits for patients suffering from COVID-19. Moreover, over above the effects of on any ERS, these drugs showed useful ancillary properties. Most showed to highlight broader roles in mitigating viral replication by the ER-independent mechanisms as mentioned. Data simplifies ER modulation an apt pharmacological approach for restricting storm and thus prevents the inflammation due to COVID-19. Mainly the application of or tissue-selective estrogen complex can provide a pharmacological response. Such treatment options can be fruitful for both sexes in the early phase of such disease condition to prevent further progression of the disease to severe forms.

Abstract 301: Angiotensin II-induced Aortic Stiffening is Associated With Upregulation of Mir-21 And Downregulation of Mir-29b

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Uwe Raaz ◽  
Ryuji Toh ◽  
Matti Adam ◽  
Futoshi Nakagami ◽  
Lars Maegdefessel ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Angiotensin Ii ◽  
Infrarenal Aorta ◽  
Arterial Remodeling ◽  
Fibrotic Response ◽  
Arterial Stiffening ◽  
Small Noncoding Rnas ◽  
Aortic Stiffening

Background Arterial stiffening is associated with aging, as well as numerous diseases such as hypertension, congestive heart failure, diabetes mellitus and renal failure, and has been identified as an independent risk factor for cardiovascular disease. Consequently there is a growing interest in the mechanisms that govern the process of arterial remodeling. Recently, small noncoding RNAs, termed microRNAs (miRs), have emerged as powerful cellular regulators involved in disease and tissue remodeling. More specifically, miR-29b downregulation as well as miR-21 upregulation have been identified as pro-fibrotic mechanisms in various cardiovascular disease models. This study investigated the role of miR-21 and miR-29b in a mouse model of AngII-induced arterial remodeling. Materials and methods Angiotensin II (AngII) (1000ng/kg/min) was infused via osmotic pumps in 10-week-old apoE-/- male mice (C57BL/6J background) for 7 days. Subsequently, arterial stiffness was determined in vivo using ultrasound-based measurements. Abdominal aortas were harvested and expression of various collagen isoforms (Col1a1, Col3a1, Col5a1) known to be crucial determinants of arterial remodeling/stiffening was quantified via qRT-PCR. We also measured expression levels of miR-21 and miR-29b. Results AngII stimulation resulted in an increased aortic stiffness paralleled by a marked pro-fibrotic response as evidenced by significant increases in Col1a1, Col3a1, and Col5a1 in the infrarenal aorta compared to baseline levels (p < 0.05). This increase was accompanied by significant downregulation of miR-29b, and upregulation of miR-21 (p <0.05). Conclusion The pro-fibrotic response in AngII-mediated arterial remodeling is associated with an increase in miR-21 and a decrease in miR-29b. Modulation of miR-21 and miR-29b have both been successful in altering fibrotic mechanisms in various cardiovascular diseases. These data suggest they may also be potential targets in the treatment of hypertensive vascular remodeling/arterial stiffening.

scholarly journals The role of angiotensin II and TGF-beta on the progression of chronic allograft nephropathy

2001 ◽  
Vol 2 (1_suppl) ◽  
pp. S188-S190
Author(s):  
Matthew R Weir ◽  
Chiming Wei
Keyword(s):  
Renal Function ◽  
Angiotensin Ii ◽  
Transforming Growth Factor ◽  
Experimental Studies ◽  
Chronic Allograft Nephropathy ◽  
Angiotensin Ii Receptor ◽  
Direct Stimulation ◽  
Converting Enzyme Inhibitors ◽  
Transplant Patients

Chronic allograft nephropathy is the most prevalent cause of graft dysfunction and failure. Its pathogenesis and treatment remains poorly defined. The calcineurin inhibitors, cyclosporine and tacrolimus, may play a role in the progressive loss of renal function in patients with chronic allograft nephropathy. This effect may be either related to the direct stimulation of profibrogenic cytokines such as transforming growth factor (TGF-β) or indirect mechanisms, through increases in blood pressure or alterations in either carbohydrate or lipid metabolism. Experimental studies have demonstrated that angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARBs) can attenuate cyclosporine-mediated increases in TGF-β production in renal tissue. Clinical studies have demonstrated that either cyclosporine or tacrolimus dose reduction may help reduce the rate of loss of renal function in patients with chronic allograft nephropathy. Moreover, other studies have demonstrated that a chronic reduction in the dose of cyclosporine in transplant patients can reduce serum TGF-β levels. Treatment with an ARB can normalise the plasma levels of TGF-β in renal transplant patients receiving cyclosporine. All these observations suggest that there may be a role of cyclosporine, and possibly tacrolimus, in worsening chronic allograft nephropathy through their effects on the renin-angiotensin-aldosterone system (RAAS) and TGF-β production.

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