Blood pressure–associated polymorphism controls ARHGAP42 expression via serum response factor DNA binding

Xue, Bai; Mangum, Kevin; Dee, Rachel; Stouffer, George A.; Lee, Craig; Oni‐Orisan, Akinyemi; Patterson, W. Cam; Schisler, Jonathan C.; Viera, Anthony J.; Taylor, Joan M.; Mack, Christopher P.

doi:10.1172/jci88899

Cited by 34 publications

(55 citation statements)

References 39 publications

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“…Both large and small arteries from GRAF3-deficient mice also exhibited increased contractility in vitro and in vivo [18]. We and others also reported that patient-specific polymorphisms in this gene are associated with human hypertension and we identified a causal mechanism by which a genetic variant controls this parameter [19][20][21][22]. As an exciting example of the clinical relevance of our work, Fjorder et al recently identified a Danish family with early onset hypertension that had a chromosomal rearrangement in GRAF3 which led to haploinsufficiency [23].…”

Section: Introductionmentioning

confidence: 51%

“…Previous studies from our lab indicate that GRAF3 limits RhoA activity in vascular SMC and endogenous GRAF3 controls SMC tone (and dampens BP) by reducing SMC calcium sensitivity and restraining expression of the SMC-specific contractile proteins that support this function [18,19,46]. When combined with a growing body of evidence that patient-specific eQTLs in the GRAF3 gene are associated with human hypertension [19,[47][48][49], these studies suggest that GRAF3 might be an attractive target for the treatment of HTN. Our current findings that modest induction of GRAF3 RQ in SMC significantly decreased basal and vasoconstrictor-induced BP and that endogenous GRAF3 can be activated by phosphorylation-induced conformational changes provide strong support for the feasibility of GRAF3 as a druggable target.…”

Section: Discussionmentioning

confidence: 80%

“…However, counter-regulatory means to control this so-called myogenic response are also important as exaggerated constriction can lead to tissue ischemia and high blood pressure. We previously reported that GRAF3 transcription is induced by the RhoA/MRTF/SRF signaling pathway that GRAF3 levels directly correlate with plasma volume (and intraluminal pressure) [19,46]. Consequently, depletion of endogenous GRAF3 exacerbated volume-overload induced increases in BP.…”

Section: Discussionmentioning

confidence: 99%

“…Vascular resistance is a major determinant of BP and is controlled, in large part, by RhoA-dependent smooth muscle cell (SMC) contraction within small peripheral arterioles [5][6][7][8]45]. Previous studies from our lab indicate that GRAF3 limits RhoA activity in vascular SMC and endogenous GRAF3 controls SMC tone (and dampens BP) by reducing SMC calcium sensitivity and restraining expression of the SMC-specific contractile proteins that support this function [18,19,46]. When combined with a growing body of evidence that patient-specific eQTLs in the GRAF3 gene are associated with human hypertension [19,[47][48][49], these studies suggest that GRAF3 might be an attractive target for the treatment of HTN.…”

Section: Discussionmentioning

confidence: 99%

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Molecular Regulation of the RhoGAP GRAF3 and Its Capacity to Limit Blood Pressure In Vivo

Dee

Xue

Mack

et al. 2020

Cells

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Anti-hypertensive therapies are usually prescribed empirically and are often ineffective. Given the prevalence and deleterious outcomes of hypertension (HTN), improved strategies are needed. We reported that the Rho-GAP GRAF3 is selectively expressed in smooth muscle cells (SMC) and controls blood pressure (BP) by limiting the RhoA-dependent contractility of resistance arterioles. Importantly, genetic variants at the GRAF3 locus controls BP in patients. The goal of this study was to validate GRAF3 as a druggable candidate for future anti-HTN therapies. Importantly, using a novel mouse model, we found that modest induction of GRAF3 in SMC significantly decreased basal and vasoconstrictor-induced BP. Moreover, we found that GRAF3 protein toggles between inactive and active states by processes controlled by the mechano-sensing kinase, focal adhesion kinase (FAK). Using resonance energy transfer methods, we showed that agonist-induced FAK-dependent phosphorylation at Y376GRAF3 reverses an auto-inhibitory interaction between the GAP and BAR-PH domains. Y376 is located in a linker between the PH and GAP domains and is invariant in GRAF3 homologues and a phosphomimetic E376GRAF3 variant exhibited elevated GAP activity. Collectively, these data provide strong support for the future identification of allosteric activators of GRAF3 for targeted anti-hypertensive therapies.

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Section: Introductionmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Molecular Regulation of the RhoGAP GRAF3 and Its Capacity to Limit Blood Pressure In Vivo

Dee

Xue

Mack

et al. 2020

Cells

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“…Moreover, endothelial nitric oxide synthase (eNOS) single-nucleotide polymorphism G894T significantly increases hypertension risk and coronary artery disease [22]. Selective expression of the Rho GTPaseactivating protein ARHGAP42 in vascular smooth muscle cells regulates arterial blood pressure, as it inhibits RhoA-dependent contractility [23]. Furthermore, PDE3A, PRDM6, IGFBP3, and KCNK3 genes regulate vascular smooth muscle cells [24].…”

Section: Arterial Hypertensionmentioning

confidence: 99%

Genetic Polymorphisms and Ischemic Heart Disease

Fedele¹,

Pucci²,

Severino³

2017

Genetic Polymorphisms

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Although the progression in diagnostic tools, prevention strategies, and therapies, ischemic heart disease still represents the major cause of mortality and morbidity worldwide that globally represents an important problem for individuals and healthcare resources. By convention, ischemic heart disease is associated with the presence of an atherosclerotic plaque that is able to limit the flow in large-medium-sized coronary arteries. Nevertheless, several findings suggest a more complex pathophysiology of ischemic heart disease. At this time, there is no well-defined assessment of myocardial ischemia pathophysiology. Moreover, several data have identified genetic variations at different loci that are linked with ischemic heart disease susceptibility. This chapter aims to examine this complicated disease and to review the evidence on the genetic heritability acting with other factors in determining the presence of ischemic heart disease, due to either an obstruction in epicardial vessels or a dysfunction of coronary microcirculation.

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Semaphorin3A Exacerbates Cardiac Microvascular Rarefaction in Pressure Overload‐Induced Heart Disease

Li,

Zhao,

et al. 2023

Advanced Science

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Microvascular endothelial cells (MiVECs) impair angiogenic potential, leading to microvascular rarefaction, which is a characteristic feature of chronic pressure overload‐induced cardiac dysfunction. Semaphorin3A (Sema3A) is a secreted protein upregulated in MiVECs following angiotensin II (Ang II) activation and pressure overload stimuli. However, its role and mechanism in microvascular rarefaction remain elusive. The function and mechanism of action of Sema3A in pressure overload‐induced microvascular rarefaction, is explored, through an Ang II‐induced animal model of pressure overload. RNA sequencing, immunoblotting analysis, enzyme‐linked immunosorbent assay, quantitative reverse transcription polymerase chain reaction (qRT‐PCR), and immunofluorescence staining results indicate that Sema3A is predominantly expressed and significantly upregulated in MiVECs under pressure overload. Immunoelectron microscopy and nano‐flow cytometry analyses indicate small extracellular vesicles (sEVs), with surface‐attached Sema3A, to be a novel tool for efficient release and delivery of Sema3A from the MiVECs to extracellular microenvironment. To investigate pressure overload‐mediated cardiac microvascular rarefaction and cardiac fibrosis in vivo, endothelial‐specific Sema3A knockdown mice are established. Mechanistically, serum response factor (transcription factor) promotes the production of Sema3A; Sema3A‐positive sEVs compete with vascular endothelial growth factor A to bind to neuropilin‐1. Therefore, MiVECs lose their ability to respond to angiogenesis. In conclusion, Sema3A is a key pathogenic mediator that impairs the angiogenic potential of MiVECs, which leads to cardiac microvascular rarefaction in pressure overload‐induced heart disease.

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Blood pressure–associated polymorphism controls ARHGAP42 expression via serum response factor DNA binding

Cited by 34 publications

References 39 publications

Molecular Regulation of the RhoGAP GRAF3 and Its Capacity to Limit Blood Pressure In Vivo

Molecular Regulation of the RhoGAP GRAF3 and Its Capacity to Limit Blood Pressure In Vivo

Genetic Polymorphisms and Ischemic Heart Disease

Semaphorin3A Exacerbates Cardiac Microvascular Rarefaction in Pressure Overload‐Induced Heart Disease

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