The CR9 element is a novel mechanical load‐responsive enhancer that regulates natriuretic peptide genes expression

Miyashita, Yohei; Tsukamoto, Osamu; Matsuoka, Ken; Kamikubo, Kenta; Kuramoto, Yuki; Fu, Haiying; Tsubota, T.; Hasuike, Hirona; Takayama, Toshio; Ito, Hiroaki; Hitsumoto, Tatsuro; Okamoto, Chisato; Kioka, Hidetaka; Oya, Ryohei; Shinomiya, Haruki; Hakui, Hideyuki; Shintani, Yasunori; Kato, Hisakazu; Kitakaze, Masafumi; Sakata, Yasushi; Asano, Yoshihiro; Takashima, Seiji

doi:10.1096/fj.202002111rr

Cited by 2 publications

(4 citation statements)

References 44 publications

(129 reference statements)

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“…Cardiomyocytes secrete NPs into the systemic circulation in response to myocardial mechanical loading 2 ; thus, the elevation of plasma NP is essential to cardiac hypertrophy or failure 1 . Previous studies have shown that plasma BNP levels are well correlated with LVMI, that is, LV hypertrophy and LV diastolic function 27,28 .…”

Section: Discussionmentioning

confidence: 99%

“…Both atrial natriuretic peptide (ANP) and B‐type natriuretic peptide (BNP), encoded by Nppa and Nppb genes, respectively, are synthesized predominantly in the cardiac myocytes and released into the systemic circulation in response to myocardial wall stretching. 1 , 2 Natriuretic peptides (NPs) exert pleiotropic effects, such as the excretion of both electrolytes and water from the kidneys, reducing vascular tone, and demonstrating anti‐hypertrophic and anti‐fibrotic effects in the heart. 1 Indeed, genetic variation in or near Nppa , Nppb , and Npra genes encoding natriuretic peptide receptor A (NPRA) are associated with regulation of either blood pressure or cardiac hypertrophy.…”

Section: Introductionmentioning

confidence: 99%

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Lower B‐type natriuretic peptide levels predict left ventricular concentric remodelling and insulin resistance

Okamoto

Tsukamoto

Hasegawa³

et al. 2021

ESC Heart Failure

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Aims Natriuretic peptides have reportedly been associated with cardiac hypertrophy and insulin resistance; however, it has not been established if B‐type natriuretic peptide (BNP) is associated with either insulin resistance or cardiac remodelling in a population with normal plasma BNP levels. We investigated the relationship among plasma BNP levels, insulin resistance, and left ventricular (LV) remodelling in a population with normal physiological plasma BNP levels. Methods and results Among 1632 individuals who participated in annual health checks between 2005 and 2008 in Arita‐cho, Saga, Japan, 675 individuals [median (interquartile range) for age 62 (51–69) years; 227 men (34%)] with LV ejection fraction 50% and BNP level <35 pg/mL were enrolled in this study. Insulin resistance was assessed using homeostatic model assessment of insulin resistance (HOMA‐IR). LV geometry, including LV concentric remodelling, was classified based on relative wall thickness (RWT) and LV mass index values derived from echocardiographic findings. Factors associated with insulin resistance and LV geometry were investigated using multiple logistic regression analysis. Tertiles of BNP were inversely associated with HOMA‐IR [1st tertile, 1.33 (0.76–1.74); 2nd tertile, 1.05 (0.72–1.59); 3rd tertile, 0.95 (0.66–1.58), P = 0.005]. Lower BNP was associated with the prevalence of insulin resistance, defined as HOMA‐IR ≥1.37, even after full multivariate adjustment [1 SD increment in BNP = adjusted odds ratio (aOR) 0.740; 95% confidence interval (CI) 0.601–0.912; P = 0.005]. LV concentric remodelling (RWT >0.42; LV mass index ≤115 g/m2 in men and ≤95 g/m2 in women) was observed in 107 (16%) participants, while normal LV geometry (RWT ≤0.42; LV mass index ≤115 g/m2 in men and ≤95 g/m2 in women) was seen in 423 (63%), and LV hypertrophy (LV mass index >115 g/m2 in men and >95 g/m2 in women) in 145 (21%). Both low BNP level and higher insulin resistance were independently linked to LV concentric remodelling after multivariate adjustment (1 SD increment in BNP = aOR 0.714, 95% CI 0.544–0.938, P = 0.015; HOMA‐IR ≥ 1.37 vs. <1.37: aOR 1.694, 95% CI 1.004–2.857, P = 0.048, respectively). Conclusions Lower BNP levels are linked to either insulin resistance or LV concentric remodelling in a population with normal plasma BNP levels, suggesting that participants with lower natriuretic peptide level might be vulnerable to the development of metabolic disorders and LV morphological abnormalities.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Lower B‐type natriuretic peptide levels predict left ventricular concentric remodelling and insulin resistance

Okamoto

Tsukamoto

Hasegawa³

et al. 2021

ESC Heart Failure

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“… 24 We previously identified the DNA regulatory element, putative enhancer CR9, for Nppa and Nppb , which responds to mechanical loads by upregulating Nppa and Nppb expression in cardiomyocytes. 2 Mice with a deletion of the regulatory DNA region, including the CR9 element, show an endocrine deficiency in ANP and BNP. 7 Accordingly, unknown variants within the regulatory DNA regions may lead to endocrine deficiencies in NPs.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the plasma natriuretic peptide (NP) levels are clinically valuable biomarkers for assessing the presence and severity of cardiac hemodynamic stress. 1 , 2 Elevated LVFP is one of the most important factors that trigger not only LV hypertrophy (LVH) but also the transcriptional activation of NPs. A positive correlation between high plasma BNP levels, LVH, and diastolic dysfunction has been demonstrated in patients with heart failure (HF) or hypertension.…”

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Relative B-Type Natriuretic Peptide Deficiency May Exist in Diastolic Dysfunction in Subclinical Population

Okamoto,

Tsukamoto,

Hasegawa

et al. 2024

Circ Rep

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Background: Heart failure patients are deficient in B-type natriuretic peptide (BNP) but the significance of subclinical BNP deficiency is unclear. Methods and Results: A total of 1,398 subjects without cardiovascular disease, with left ventricular ejection fraction (LVEF) ≥50% and BNP level <100 pg/mL, were selected from a 2005–2008 health checkup in Arita-cho, Japan, and divided into 2 groups: with and without LV diastolic dysfunction (DD+ or DD−). We performed propensity score matching on non-cardiac factors affecting BNP levels and analyzed 470 subjects in each group (372/940 men; median age, 66 years). The DD(+) group showed higher lateral E/e', an index of estimated left ventricular filling pressure, and greater prevalence of concentric hypertrophy (CH) despite similar BNP levels, suggesting a relative deficiency of BNP in DD(+) compared with DD(−). Multivariable logistic regression analysis revealed an increase in BNP correlated with decreased odds of CH (adjusted odds ratio [aOR] 0.663, 95% confidence interval (CI) 0.484–0.909, P=0.011), whereas an increase in lateral E/e' was associated with increased odds of CH (aOR, 2.881; 95% CI, 1.390–5.973; P=0.004). Furthermore, CH in combination with diastolic dysfunction independently predicted major adverse cardiovascular events (hazard ratio 3.272, 95% CI 1.215–8.809; P=0.019). Conclusions: Relative BNP deficiency was associated with CH, which had a poor prognosis in patients with diastolic dysfunction.

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The CR9 element is a novel mechanical load‐responsive enhancer that regulates natriuretic peptide genes expression

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 2 publications

References 44 publications

Lower B‐type natriuretic peptide levels predict left ventricular concentric remodelling and insulin resistance

Lower B‐type natriuretic peptide levels predict left ventricular concentric remodelling and insulin resistance

Relative B-Type Natriuretic Peptide Deficiency May Exist in Diastolic Dysfunction in Subclinical Population

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