Investigating inherent functional differences between human cardiac fibroblasts cultured from nondiabetic and Type 2 diabetic donors

Sedgwick, Bryony; Riches, Kirsten; Bageghni, Sumia A.; O’Regan, David; Porter, Karen E.; Turner, Neil A.

doi:10.1016/j.carpath.2014.03.004

Cited by 42 publications

(26 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Diabetes-associated generation of reactive oxygen species, activation of AGE (advanced glycation end-products)-RAGE (receptor for AGE) signaling, and stimulation of angiotensin II or growth factor pathways may activate atrial fibroblasts triggering left atrial fibrosis (45). In patients with coronary disease, diabetes was associated with an activated atrial fibroblast phenotype, showing a 2-fold increase in collagen transcription (46). …”

Section: 4 Discussionmentioning

confidence: 99%

Left atrial remodeling, hypertrophy, and fibrosis in mouse models of heart failure

Hanif¹,

Alex²,

Su³

et al. 2017

Cardiovascular Pathology

View full text Add to dashboard Cite

Left ventricular dysfunction increases left atrial pressures and causes atrial remodeling. In human subjects, increased left atrial size is a powerful predictor of mortality and adverse events in a broad range of cardiac pathologic conditions. Moreover, structural remodeling of the atrium plays an important role in the pathogenesis of atrial tachyarrhythmias. Despite the potential value of the atrium in assessment of functional endpoints in myocardial disease, atrial pathologic alterations in mouse models of left ventricular disease have not been systematically investigated. Our study describes the geometric, morphologic and structural changes in experimental mouse models of cardiac pressure overload (induced through transverse aortic constriction), myocardial infarction and diabetes. Morphometric and histological analysis showed that pressure overload was associated with left atrial dilation, increased left atrial mass, loss of myofibrillar content in a subset of atrial cardiomyocytes, atrial cardiomyocyte hypertrophy, and atrial fibrosis. In mice undergoing non-reperfused myocardial infarction protocols, marked left ventricular systolic dysfunction was associated with left atrial enlargement, atrial cardiomyocyte hypertrophy and atrial fibrosis. Both infarcted animals and pressure overloaded mice exhibited attenuation and perturbed localization of atrial connexin-43 immunoreactivity, suggesting gap junctional remodeling. In the absence of injury, obese diabetic db/db mice had diastolic dysfunction, associated with atrial dilation, atrial cardiomyocyte hypertrophy and mild atrial fibrosis. Considering the challenges in assessment of clinically relevant functional endpoints in mouse models of heart disease, study of atrial geometry and morphology may serve as an important new tool for evaluation of ventricular function.

show abstract

Section: 4 Discussionmentioning

confidence: 99%

Left atrial remodeling, hypertrophy, and fibrosis in mouse models of heart failure

Hanif¹,

Alex²,

Su³

et al. 2017

Cardiovascular Pathology

View full text Add to dashboard Cite

show abstract

“…Cardiac fibroblasts isolated from db/db mice exhibited a matrix-preserving phenotype, associated with increased expression of collagen and protease inhibitors [51]. Atrial fibroblasts derived from patients with type 2 diabetes also showed evidence of activation, exhibiting high collagen synthesis [52]. Hyperglycemia, activation of the Renin-angiotensin-aldosterone (RAAS) system and fibrogenic growth factors induced by metabolic dysregulation may be involved in activation of cardiac fibroblasts in diabetic hearts.…”

Section: The Cell Biology Of Diabetes-associated Cardiac Fibrosismentioning

confidence: 99%

Diabetes-associated cardiac fibrosis: Cellular effectors, molecular mechanisms and therapeutic opportunities

Russo

Frangogiannis

2016

Journal of Molecular and Cellular Cardiology

356

299

View full text Add to dashboard Cite

Both type 1 and type 2 diabetes are associated with cardiac fibrosis that may reduce myocardial compliance, contribute to the pathogenesis of heart failure, and trigger arrhythmic events. Diabetes-associated fibrosis is mediated by activated cardiac fibroblasts, but may also involve fibrogenic actions of macrophages, cardiomyocytes and vascular cells. The molecular basis responsible for cardiac fibrosis in diabetes remains poorly understood. Hyperglycemia directly activates a fibrogenic program, leading to accumulation of advanced glycation end-products (AGEs) that crosslink extracellular matrix proteins, and transduce fibrogenic signals through reactive oxygen species generation, or through activation of Receptor for AGEs (RAGE)-mediated pathways. Pro-inflammatory cytokines and chemokines may recruit fibrogenic leukocyte subsets in the cardiac interstitium. Activation of transforming growth factor-β/Smad signaling may activate fibroblasts inducing deposition of structural extracellular matrix proteins and matricellular macromolecules. Adipokines, endothelin-1 and the renin-angiotensin-aldosterone system have also been implicated in the diabetic myocardium. This manuscript reviews our current understanding of the cellular effectors and molecular pathways that mediate fibrosis in diabetes. Based on the pathophysiologic mechanism, we propose therapeutic interventions that may attenuate the diabetes-associated fibrotic response and discuss the challenges that may hamper clinical translation.

show abstract

“…This increased collagen production is also true of cardiac fibroblasts isolated from an in vivo diabetic state and then cultured. For example, when compared to fibroblasts from non-diabetic individuals, collagen I production was increased from isolated right-atrial cardiac fibroblasts obtained from diabetic individuals without left-ventricular dysfunction, undergoing coronary artery bypass graft surgery [26]. Similarly, cardiac fibroblasts isolated from diabetic rodent models produce excess ECM when cultured.…”

Section: Extracellular Matrix Productionmentioning

confidence: 99%

The Diabetic Cardiac Fibroblast: Mechanisms Underlying Phenotype and Function

Levick

Widiapradja

2020

IJMS

View full text Add to dashboard Cite

Diabetic cardiomyopathy involves remodeling of the heart in response to diabetes that includes microvascular damage, cardiomyocyte hypertrophy, and cardiac fibrosis. Cardiac fibrosis is a major contributor to diastolic dysfunction that can ultimately result in heart failure with preserved ejection fraction. Cardiac fibroblasts are the final effector cell in the process of cardiac fibrosis. This review article aims to describe the cardiac fibroblast phenotype in response to high-glucose conditions that mimic the diabetic state, as well as to explain the pathways underlying this phenotype. As such, this review focuses on studies conducted on isolated cardiac fibroblasts. We also describe molecules that appear to oppose the pro-fibrotic actions of high glucose on cardiac fibroblasts. This represents a major gap in knowledge in the field that needs to be addressed.

show abstract

Investigating inherent functional differences between human cardiac fibroblasts cultured from nondiabetic and Type 2 diabetic donors

Cited by 42 publications

References 39 publications

Left atrial remodeling, hypertrophy, and fibrosis in mouse models of heart failure

Left atrial remodeling, hypertrophy, and fibrosis in mouse models of heart failure

Diabetes-associated cardiac fibrosis: Cellular effectors, molecular mechanisms and therapeutic opportunities

The Diabetic Cardiac Fibroblast: Mechanisms Underlying Phenotype and Function

Contact Info

Product

Resources

About