Hypertension

Madhur, Meena S; Elijovich, Fernando; Alexander, Matthew; Pitzer, Ashley; Ishimwe, Jeanne; Beusecum, Justin P Van; Patrick, David M.; Smart, Charles D; Kleyman, Thomas R.; Kingery, Justin R; Peck, Robert; Laffer, Cheryl L.; Kirabo, Annet

doi:10.1161/circresaha.121.318052

Cited by 134 publications

(50 citation statements)

References 267 publications

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“…Given the important role of immune cells in hypertension 7,28 and that the rs3184504 minor allele is strongly associated with increased circulating leukocyte counts in humans, 29 we examined circulating blood cell counts in Arg/Arg and Trp/Trp mice after 4 weeks of Ang II infusion. Increases in total leukocytes (Figure 4A), monocytes (Figure 4B), lymphocytes (Figure 4C), and neutrophils (Figure 4D) were observed in Trp/Trp mice compared with controls and splenomegaly was greater (Figure 4E).…”

Section: Resultsmentioning

confidence: 99%

A Single Nucleotide Polymorphism in SH2B3/LNK Promotes Hypertension Development and Renal Damage

Alexander

Hank

Dale

et al. 2022

Circulation Research

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Rationale: SH2B3 (SH2B adaptor protein 3) is an adaptor protein that negatively regulates cytokine signaling and cell proliferation. A common missense single-nucleotide polymorphism in SH2B3 (rs3184504) results in substitution of tryptophan for arginine at amino acid 262 and is a top association signal for hypertension in human genome-wide association studies. Whether this variant is causal for hypertension, and if so, the mechanism by which it impacts pathogenesis is unknown. Objectives: Test the hypothesis that the tryptophan-encoding allele of rs3184504 promotes hypertension development and end-organ damage through loss of SH2B3-mediated repression of cytokine signaling to enhance T-cell activation. Methods and Results: We used CRISPR-Cas9 technology to create mice homozygous for the major (arginine/arginine) and minor (tryptophan/tryptophan) alleles of this SH2B3 polymorphism. Tryptophan/tryptophan mice exhibited 10 mm Hg higher systolic blood pressure during chronic Ang II (angiotensin II) infusion compared with arginine/arginine controls. Renal injury and perivascular fibrosis were exacerbated in tryptophan/tryptophan mice compared with arginine/arginine controls following Ang II infusion. In addition, renal and ex vivo stimulated splenic CD8 + T cells from Ang II–infused tryptophan/tryptophan mice produced significantly more IFN (interferon)-γ compared with arginine/arginine controls. IL (Interleukin)-12-induced IFN-γ production was greater in tryptophan/tryptophan compared with arginine/arginine CD8 + T cells. In addition, IL-12 enhanced Stat4 (signal transducer and activator of transcription 4) phosphorylation to a greater degree in tryptophan/tryptophan compared with arginine/arginine CD8 + T cells, suggesting that tryptophan-encoding SH2B3 exhibits less negative regulation of IL-12 signaling to promote IFN-γ production. Finally, we demonstrated that a multi-single-nucleotide polymorphism model genetically predicting increased SH2B3 expression in lymphocytes is inversely associated with hypertension and hypertensive chronic kidney disease in humans. Conclusions: Taken together, these results suggest that the tryptophan-encoding allele of rs3184504 is causal for blood pressure elevation and renal dysfunction, in part through loss of SH2B3-mediated repression of T-cell IL-12 signaling leading to enhanced IFN-γ production.

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Section: Resultsmentioning

confidence: 99%

A Single Nucleotide Polymorphism in SH2B3/LNK Promotes Hypertension Development and Renal Damage

Alexander

Hank

Dale

et al. 2022

Circulation Research

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“…Generally, pathogen infection could be one of the inflammatory triggering factors that is connected with the incidence and development of arterial hypertension, including abnormal systolic and/or diastolic pressure [58,59]. Chronic stimulation of inflammatory reactions owing to bacterial infection in the gastrointestinal tract generates induction of MetS-related dyslipidemia, triggers release of C-reactive protein (CRP), escalates blood leukocytes and MetS-related homocysteine, increases the concentrations of MetS-related fibrinogen, induces hypercoagulability, stimulates immune cross-reactivity, and rises proinflammatory cytokines and other cytotoxic agents.…”

Section: H Pylori-related Arterial Hypertensionmentioning

confidence: 99%

Impact of Helicobacter pylori-Related Metabolic Syndrome Parameters on Arterial Hypertension

et al. 2021

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Arterial hypertension is a risk factor for several pathologies, mainly including cardio-cerebrovascular diseases, which rank as leading causes of morbidity and mortality worldwide. Arterial hypertension also constitutes a fundamental component of the metabolic syndrome. Helicobacter pylori infection is one of the most common types of chronic infection globally and displays a plethora of both gastric and extragastric effects. Among other entities, Helicobacter pylori has been implicated in the pathogenesis of the metabolic syndrome. Within this review, we illustrate the current state-of-the-art evidence, which may link several components of the Helicobacter pylori-related metabolic syndrome, including non-alcoholic fatty liver disease and arterial hypertension. In particular, current knowledge of how Helicobacter pylori exerts its virulence through dietary, inflammatory and metabolic pathways will be discussed. Although there is still no causative link between these entities, the emerging evidence from both basic and clinical research supports the proposal that several components of the Helicobacter pylori infection-related metabolic syndrome present an important risk factor in the development of arterial hypertension. The triad of Helicobacter pylori infection, the metabolic syndrome, and hypertension represents a crucial worldwide health problem on a pandemic scale with high morbidity and mortality, like COVID-19, thereby requiring awareness and appropriate management on a global scale.

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“…Hypertension, or high blood pressure, is a multifactorial disease related to genetic, environmental, demographic, lifestyle, vascular, and neuroendocrine disorders; and is a serious medical condition that can increase the risk of heart, brain, kidney, and other diseases, thus making it a major cause of premature death worldwide [1][2][3][4][5][6]. Based on the most recent WHO report in 21 May 2021, an estimated 1.13 billion people worldwide have hypertension, and less than 20% of these individuals have the problem under control (https://www.who.int/news-room/fact-sheets/detail/hypertension, accessed on 21 May 2021).…”

Section: Introductionmentioning

confidence: 99%

“…Despite many years of efforts, hypertension remains one of the most challenging disorders to study and treat due to the complex nature and unknown cause, thus intensifying the need for more investigations to identify the factors or molecular signaling that cause most of these disorders [7]. One of the advancements in this field is the discovery of possible inter-relationships between the various interleukins and the development of high blood pressure [1,8]. Specifically, a growing amount of evidence points to a possible link between hypertension and interleukin-1β (IL-1β), a well-characterized mediator of inflammation.…”

Section: Introductionmentioning

confidence: 99%

Interleukin-1β in Multifactorial Hypertension: Inflammation, Vascular Smooth Muscle Cell and Extracellular Matrix Remodeling, and Non-Coding RNA Regulation

Melton

Qiu

2021

IJMS

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The biological activities of interleukins, a group of circulating cytokines, are linked to the immuno-pathways involved in many diseases. Mounting evidence suggests that interleukin-1β (IL-1β) plays a significant role in the pathogenesis of various types of hypertension. In this review, we summarized recent findings linking IL-1β to systemic arterial hypertension, pulmonary hypertension, and gestational hypertension. We also outlined the new progress in elucidating the potential mechanisms of IL-1β in hypertension, focusing on it’s regulation in inflammation, vascular smooth muscle cell function, and extracellular remodeling. In addition, we reviewed recent studies that highlight novel findings examining the function of non-coding RNAs in regulating the activity of IL-1β and its associated proteins in the setting of hypertension. The information collected in this review provides new insights into understanding the pathogenesis of hypertension and could lead to the discovery of new anti-hypertensive therapies to combat this highly prevalent disease.

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Hypertension

Cited by 134 publications

References 267 publications

A Single Nucleotide Polymorphism in SH2B3/LNK Promotes Hypertension Development and Renal Damage

A Single Nucleotide Polymorphism in SH2B3/LNK Promotes Hypertension Development and Renal Damage

Impact of Helicobacter pylori-Related Metabolic Syndrome Parameters on Arterial Hypertension

Interleukin-1β in Multifactorial Hypertension: Inflammation, Vascular Smooth Muscle Cell and Extracellular Matrix Remodeling, and Non-Coding RNA Regulation

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