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Signature of diabetic cardiomyopathy progression using high-fat diet and streptozotocin mouse model: from subclinical to clinical with three-hit mouse model

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Title: Signature of diabetic cardiomyopathy progression using high-fat diet and streptozotocin mouse model: from subclinical to clinical with three-hit mouse model
Authors: N Karuna, L Kerrigan, K Edgar, C Tonry, D Grieve, C Watson
Source: European Heart Journal. 45
Publisher Information: Oxford University Press (OUP), 2024.
Publication Year: 2024
Description: Background Diabetic cardiomyopathy (DbCM) is a pre-heart failure (pre-HF) condition that usually exhibits early diastolic dysfunction and evolving systolic dysfunction, along with left ventricular (LV) remodelling. Although DbCM shows distinct pathophysiology, the transition from the subclinical to the symptomatic stage is not straightforward and usually involves multifaceted processes which are not fully understood. Purpose To define the signature of DbCM progression in a novel mouse model using longitudinal echocardiography and multi-omics approaches. Methods Male mice (C57BL/6) were fed with high-fat diet (HFD) or control diet (CD) for 24 weeks, with single dose of streptozotocin (STZ) or vehicle injection at 8 weeks (n=10 each). Serial functional and metabolic parameters were measured prior to endpoint single nuclei RNA sequencing (snRNA-seq) and mass spectrometry-based proteomics analysis with comparison to cardiac remodelling to define detailed mechanisms underlying DbCM progression. Results HFD/STZ mice developed type 2 diabetes mellitus (T2DM) based on higher fasting blood glucose and HbA1C levels, insulin resistance and decreased beta-cell function (HOMA-IR and HOMA-beta, respectively) compared to controls. Progressive diastolic dysfunction was evident in HFD/STZ mice compared to CD mice based on enlarged LVPW;d from 12 weeks (P Conclusion Our HFD/STZ mouse model offers a ‘three-hit’ approach which effectively captures key stages of clinical DbCM progression: 1) T2DM with insulin resistance, 2) progressive diastolic dysfunction with elevated chronic filling pressure and cardiac remodelling, and 3) systemic inflammation. This improved HFD/STZ mouse model is therefore appropriate to support a detailed study of mechanisms underlying DbCM progression and subsequent translation.
Document Type: Article
Language: English
ISSN: 1522-9645
0195-668X
DOI: 10.1093/eurheartj/ehae666.3781
Rights: OUP Standard Publication Reuse
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  Data: Signature of diabetic cardiomyopathy progression using high-fat diet and streptozotocin mouse model: from subclinical to clinical with three-hit mouse model
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  Data: <searchLink fieldCode="AR" term="%22N+Karuna%22">N Karuna</searchLink><br /><searchLink fieldCode="AR" term="%22L+Kerrigan%22">L Kerrigan</searchLink><br /><searchLink fieldCode="AR" term="%22K+Edgar%22">K Edgar</searchLink><br /><searchLink fieldCode="AR" term="%22C+Tonry%22">C Tonry</searchLink><br /><searchLink fieldCode="AR" term="%22D+Grieve%22">D Grieve</searchLink><br /><searchLink fieldCode="AR" term="%22C+Watson%22">C Watson</searchLink>
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  Data: <i>European Heart Journal</i>. 45
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  Data: Background Diabetic cardiomyopathy (DbCM) is a pre-heart failure (pre-HF) condition that usually exhibits early diastolic dysfunction and evolving systolic dysfunction, along with left ventricular (LV) remodelling. Although DbCM shows distinct pathophysiology, the transition from the subclinical to the symptomatic stage is not straightforward and usually involves multifaceted processes which are not fully understood. Purpose To define the signature of DbCM progression in a novel mouse model using longitudinal echocardiography and multi-omics approaches. Methods Male mice (C57BL/6) were fed with high-fat diet (HFD) or control diet (CD) for 24 weeks, with single dose of streptozotocin (STZ) or vehicle injection at 8 weeks (n=10 each). Serial functional and metabolic parameters were measured prior to endpoint single nuclei RNA sequencing (snRNA-seq) and mass spectrometry-based proteomics analysis with comparison to cardiac remodelling to define detailed mechanisms underlying DbCM progression. Results HFD/STZ mice developed type 2 diabetes mellitus (T2DM) based on higher fasting blood glucose and HbA1C levels, insulin resistance and decreased beta-cell function (HOMA-IR and HOMA-beta, respectively) compared to controls. Progressive diastolic dysfunction was evident in HFD/STZ mice compared to CD mice based on enlarged LVPW;d from 12 weeks (P Conclusion Our HFD/STZ mouse model offers a ‘three-hit’ approach which effectively captures key stages of clinical DbCM progression: 1) T2DM with insulin resistance, 2) progressive diastolic dysfunction with elevated chronic filling pressure and cardiac remodelling, and 3) systemic inflammation. This improved HFD/STZ mouse model is therefore appropriate to support a detailed study of mechanisms underlying DbCM progression and subsequent translation.
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