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HuR/Cx40 downregulation causes coronary microvascular dysfunction in type 2 diabetes.

ABSTRACT: Patients with diabetes with coronary microvascular disease (CMD) exhibit higher cardiac mortality than patients without CMD. However, the molecular mechanism by which diabetes promotes CMD is poorly understood. RNA-binding protein human antigen R (HuR) is a key regulator of mRNA stability and translation; therefore, we investigated the role of HuR in the development of CMD in mice with type 2 diabetes. Diabetic mice exhibited decreases in coronary flow velocity reserve (CFVR; a determinant of coronary microvascular function) and capillary density in the left ventricle. HuR levels in cardiac endothelial cells (CECs) were significantly lower in diabetic mice and patients with diabetes than the controls. Endothelial-specific HuR-KO mice also displayed significant reductions in CFVR and capillary density. By examining mRNA levels of 92 genes associated with endothelial function, we found that HuR, Cx40, and Nox4 levels were decreased in CECs from diabetic and HuR-KO mice compared with control mice. Cx40 expression and HuR binding to Cx40 mRNA were downregulated in CECs from diabetic mice. Cx40-KO mice exhibited decreased CFVR and capillary density, whereas endothelium-specific Cx40 overexpression increased capillary density and improved CFVR in diabetic mice. These data suggest that decreased HuR contributes to the development of CMD in diabetes through downregulation of gap junction protein Cx40 in CECs.

SUBMITTER: Si R

PROVIDER: S-EPMC8663561 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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HuR/Cx40 downregulation causes coronary microvascular dysfunction in type 2 diabetes.

Si Rui R Cabrera Jody Tori O JTO Tsuji-Hosokawa Atsumi A Guo Rui R Watanabe Makiko M Gao Lei L Lee Yun Sok YS Moon Jae-Su JS Scott Brian T BT Wang Jian J Ashton Anthony W AW Rao Jaladanki N JN Wang Jian-Ying JY Yuan Jason X-J JX Makino Ayako A

JCI insight 20211108 21

Patients with diabetes with coronary microvascular disease (CMD) exhibit higher cardiac mortality than patients without CMD. However, the molecular mechanism by which diabetes promotes CMD is poorly understood. RNA-binding protein human antigen R (HuR) is a key regulator of mRNA stability and translation; therefore, we investigated the role of HuR in the development of CMD in mice with type 2 diabetes. Diabetic mice exhibited decreases in coronary flow velocity reserve (CFVR; a determinant of co ...[more]

PMID: 34747371

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Project description:BackgroundType 2 diabetes (T2D) and hypertension commonly coexist and are associated with subclinical myocardial structural and functional changes. We sought to determine the association between blood pressure (BP) and left ventricular (LV) remodeling, systolic/diastolic function, and coronary microvascular function, among individuals with T2D without prevalent cardiovascular disease.MethodsParticipants with T2D and age-, sex-, and ethnicity-matched controls underwent comprehensive cardiovascular phenotyping including fasting bloods, transthoracic echocardiography, cardiovascular magnetic resonance imaging with quantitative adenosine stress/rest perfusion, and office and 24-h ambulatory BP monitoring. Multivariable linear regression was performed to determine independent associations between BP and imaging markers of remodeling and function in T2D.ResultsIndividuals with T2D (n = 205, mean age 63 ± 7 years) and controls (n = 40, mean age 61 ± 8 years) were recruited. Mean 24-h systolic BP, but not office BP, was significantly greater among those with T2D compared to controls (128.8 ± 11.7 vs 123.0 ± 13.1 mmHg, p = 0.006). Those with T2D had concentric LV remodeling (mass/volume 0.91 ± 0.15 vs 0.82 ± 0.11 g/mL, p < 0.001), decreased myocardial perfusion reserve (2.82 ± 0.83 vs 3.18 ± 0.82, p = 0.020), systolic dysfunction (global longitudinal strain 16.0 ± 2.3 vs 17.2 ± 2.1%, p = 0.004) and diastolic dysfunction (E/e' 9.30 ± 2.43 vs 8.47 ± 1.53, p = 0.044) compared to controls. In multivariable regression models adjusted for 14 clinical variables, mean 24-h systolic BP was independently associated with concentric LV remodeling (β = 0.165, p = 0.031), diastolic dysfunction (β = 0.273, p < 0.001) and myocardial perfusion reserve (β = - 0.218, p = 0.016). Mean 24-h diastolic BP was associated with LV concentric remodeling (β = 0.201, p = 0.016).Conclusion24-h ambulatory systolic BP, but not office BP, is independently associated with cardiac remodeling, coronary microvascular dysfunction, and diastolic dysfunction among asymptomatic individuals with T2D. (Clinical trial registration. URL: https://clinicaltrials.gov/ct2/show/NCT03132129 Unique identifier: NCT03132129).

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HuR/Cx40 downregulation causes coronary microvascular dysfunction in type 2 diabetes.

Publications

HuR/Cx40 downregulation causes coronary microvascular dysfunction in type 2 diabetes.

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