Hypertension and increased endothelial mechanical stretch promote monocyte differentiation and activation: roles of STAT3, interleukin 6 and hydrogen peroxide

Loperena, Roxana; Beusecum, Justin P Van; Itani, Hana A.; Engel, Noah; Laroumanie, Fanny; Xiao, Liang; Elijovich, Fernando; Laffer, Cheryl L.; Gnecco, Juan; Noonan, Jonathan; Maffia, Pasquale; Jasiewicz-Honkisz, Barbara; Cześnikiewicz-Guzik, Marta; Mikołajczyk, T.; Śliwa, Tomasz; Dikalov, Sergey; Weyand, Cornelia M.; Guzik, Tomasz J.; Harrison, David G.

doi:10.1093/cvr/cvy112

Cited by 127 publications

(85 citation statements)

References 66 publications

(83 reference statements)

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“…This is in line with earlier observations that T cell activation and vascular recruitment depend on pressure increase and are in part dependent on mechanical stretch, 11 which involves and affects antigen presenting cell activation. 29 Taking into account that miR-214 increases in T cells upon activation and perivascular T cell infiltration increases 3-to 4-fold in hypertension, T cell infiltration into PVAT may provide the most compelling mechanism of miR-214 increase in this compartment in Ang II-induced hypertension. Moreover, miR-214 seems to regulate T cell activation characterized by profibrotic effector cytokine production and chemokine receptor expression.…”

Section: Discussionmentioning

confidence: 99%

T-Cell–Derived miRNA-214 Mediates Perivascular Fibrosis in Hypertension

Nosalski

Siedliński

Denby

et al. 2020

Circulation Research

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Despite increasing understanding of the prognostic importance of vascular stiffening linked to perivascular fibrosis in hypertension, the molecular and cellular regulation of this process is poorly understood. OBJECTIVES: To study the functional role of microRNA-214 (miR-214) in the induction of perivascular fibrosis and endothelial dysfunction driving vascular stiffening. METHODS AND RESULTS: Out of 381 miRs screened in the perivascular tissues in response to Ang II (angiotensin II)-mediated hypertension, miR-214 showed the highest induction (8-fold, P=0.0001). MiR-214 induction was pronounced in perivascular and circulating T cells, but not in perivascular adipose tissue adipocytes. Global deletion of miR-214 −/− prevented Ang II-induced periaortic fibrosis, Col1a1, Col3a1, Col5a1, and Tgfb1 expression, hydroxyproline accumulation, and vascular stiffening, without difference in blood pressure. Mechanistic studies revealed that miR-214 −/− mice were protected against endothelial dysfunction, oxidative stress, and increased Nox2, all of which were induced by Ang II in WT mice. Ang IIinduced recruitment of T cells into perivascular adipose tissue was abolished in miR-214 −/− mice. Adoptive transfer of miR-214 −/− T cells into RAG1 −/− mice resulted in reduced perivascular fibrosis compared with the effect of WT T cells. Ang II induced hypertension caused significant change in the expression of 1380 T cell genes in WT, but only 51 in miR-214 −/−. T cell activation, proliferation and chemotaxis pathways were differentially affected. MiR-214 −/− prevented Ang II-induction of profibrotic T cell cytokines (IL-17, TNF-α, IL-9, and IFN-γ) and chemokine receptors (CCR1, CCR2, CCR4, CCR5, CCR6, and CXCR3). This manifested in reduced in vitro and in vivo T cell chemotaxis resulting in attenuation of profibrotic perivascular inflammation. Translationally, we show that miR-214 is increased in plasma of patients with hypertension and is directly correlated to pulse wave velocity as a measure of vascular stiffness. CONCLUSIONS: T-cell-derived miR-214 controls pathological perivascular fibrosis in hypertension mediated by T cell recruitment and local profibrotic cytokine release. VISUAL OVERVIEW: An online visual overview is available for this article.

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Section: Discussionmentioning

confidence: 99%

T-Cell–Derived miRNA-214 Mediates Perivascular Fibrosis in Hypertension

Nosalski

Siedliński

Denby

et al. 2020

Circulation Research

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“…Another mechanism linking hypertension and COVID-19 is the immune system, which is dysregulated in hypertension and SARS-CoV-2 infection. 39,40 Poor control of blood pressure may contribute to further dysregulation of the immune system. For example, it has been shown that hypertension, in humans, is associated with circulating lymphocyte counts, 41 and CD8þ T cell dysfunction is observed in patients with hypertension 42 .…”

Section: Covid-19 and Hypertensionmentioning

confidence: 99%

COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options

Guzik

Mohiddin

Dimarco³

et al. 2020

Cardiovascular Research

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The novel coronavirus disease (COVID-19) outbreak, caused by SARS-CoV-2, represents the greatest medical challenge in decades. We provide a comprehensive review of the clinical course of COVID-19, its comorbidities, and mechanistic considerations for future therapies. While COVID-19 primarily affects the lungs, causing interstitial pneumonitis and severe acute respiratory distress syndrome (ARDS), it also affects multiple organs, particularly the cardiovascular system. Risk of severe infection and mortality increase with advancing age and male sex. Mortality is increased by comorbidities: cardiovascular disease, hypertension, diabetes, chronic pulmonary disease, and cancer. The most common complications include arrhythmia (atrial fibrillation, ventricular tachyarrhythmia, and ventricular fibrillation), cardiac injury [elevated highly sensitive troponin I (hs-cTnI) and creatine kinase (CK) levels], fulminant myocarditis, heart failure, pulmonary embolism, and disseminated intravascular coagulation (DIC). Mechanistically, SARS-CoV-2, following proteolytic cleavage of its S protein by a serine protease, binds to the transmembrane angiotensin-converting enzyme 2 (ACE2) —a homologue of ACE—to enter type 2 pneumocytes, macrophages, perivascular pericytes, and cardiomyocytes. This may lead to myocardial dysfunction and damage, endothelial dysfunction, microvascular dysfunction, plaque instability, and myocardial infarction (MI). While ACE2 is essential for viral invasion, there is no evidence that ACE inhibitors or angiotensin receptor blockers (ARBs) worsen prognosis. Hence, patients should not discontinue their use. Moreover, renin–angiotensin–aldosterone system (RAAS) inhibitors might be beneficial in COVID-19. Initial immune and inflammatory responses induce a severe cytokine storm [interleukin (IL)-6, IL-7, IL-22, IL-17, etc.] during the rapid progression phase of COVID-19. Early evaluation and continued monitoring of cardiac damage (cTnI and NT-proBNP) and coagulation (D-dimer) after hospitalization may identify patients with cardiac injury and predict COVID-19 complications. Preventive measures (social distancing and social isolation) also increase cardiovascular risk. Cardiovascular considerations of therapies currently used, including remdesivir, chloroquine, hydroxychloroquine, tocilizumab, ribavirin, interferons, and lopinavir/ritonavir, as well as experimental therapies, such as human recombinant ACE2 (rhACE2), are discussed.

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“…101 It has been observed that increased stretch of hypertensive arteries activates endothelium, releasing IL-6, IL-23 and ROS whilst reducing nitric oxide (NO), and favouring STAT3 activation. 100 Studies have also showed that isoketals (or isolevuglandins, derived from free radical-mediated lipid peroxidation) accumulate in DCs in hypertension, promoting cytokine production and being able to act as neoantigens when adducted to proteins, activating DCs. 98,99 These isoketalmodified proteins have been found to be elevated in circulating monocytes and DCs from hypertensive patients.…”

Section: Hypertensionmentioning

confidence: 99%

The role of the interleukin‐23/Th17 pathway in cardiometabolic comorbidity associated with psoriasis

Egeberg

Gisondi

Carrascosa

et al. 2020

Acad Dermatol Venereol

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Alterations in the innate and adaptive immunity underpin psoriasis pathophysiology, with the Th17 cells subset now recognized as the fundamental cells in the key controlling pathway involved in its pathogenesis. Since psoriasis is a systemic disease with important comorbidity, further knowledge on the interleukin (IL)-23/Th17 axis led to the hypothesis that there may be shared pathogenic pathways between primary skin disease and comorbidity. Psoriasis has been identified as a risk factor for cardiovascular and metabolic disease, and increasing evidence gives support to this epidemiological observation from the clinical-pathologically field. As an example, increased levels of IL-23 and IL-23R have been found in human atherosclerotic plaque, and levels correlated with symptom duration and mortality. Also, upregulation of IL-23/IL-17 seems to play an important role in both myocardial damage and stroke, with interesting reports on deleterious effect neutralization after administration of related anti-bodies in both associated conditions. In diabetic patients, increased levels of IL-23/IL-17 have also been observed and available data support a synergistic role of IL-23/IL-17 in b-cells damage. In obesity, signs of an expansion of Th17 subset in adipose tissue have been reported, as well as elevated concentrations of IL-23 in obese patients. In non-alcoholic fatty liver disease, closely related to metabolic syndrome, but also in other mentioned cardiometabolic disorders, a predominance of IL-23 and other related proinflammatory factors has been identified as participating in their pathogenesis. Thus, the involvement of the IL-23/Th17 axis in these shared psoriasis-cardiometabolic pathogenic mechanisms is reviewed and discussed in the light of the existing preclinical and clinical evidence, including that from comorbid psoriasis patients.

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Hypertension and increased endothelial mechanical stretch promote monocyte differentiation and activation: roles of STAT3, interleukin 6 and hydrogen peroxide

Cited by 127 publications

References 66 publications

T-Cell–Derived miRNA-214 Mediates Perivascular Fibrosis in Hypertension

T-Cell–Derived miRNA-214 Mediates Perivascular Fibrosis in Hypertension

COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options

The role of the interleukin‐23/Th17 pathway in cardiometabolic comorbidity associated with psoriasis

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