Cardiac fibroblast activation and hyaluronan synthesis in response to hyperglycemia and diet-induced insulin resistance

Abstract

Diabetic patients are at a greater risk of heart failure due to diabetic cardiomyopathy and worsened outcome post-myocardial infarction. While the molecular mechanisms remain unclear, fibrosis and chronic inflammation are common characteristics of both conditions. Diabetes mellitus (types I and II) results in excessive hyaluronan (HA) deposition in vivo, and hyperglycemia stimulates HA synthesis for several cell types in vitro. HA-rich extracellular matrix contributes to fibrotic, hyperplastic and inflammatory disease progression. We hypothesized that excessive hyperglycemia-driven HA accumulation may contribute to pathological fibroblast activation and fibrotic remodelling in diabetic patients. Therefore, we analysed the impact of both hyperglycemia and diet-induced obesity and insulin resistance on HA matrix formation and cardiac fibroblast activation. Here we report that cardiac fibroblasts isolated from mice on a diabetogenic diet acquire pro-fibrotic gene expression without a concomitant increase in HA matrix deposition. Additionally, hyperglycemia alone does not stimulate HA synthesis or cardiac fibroblast activation in vitro, suggesting that the direct effect of hyperglycemia on fibroblasts is not the primary driver of fibrotic remodelling in cardiac diabetic maladaptation.

Crosstalk of Diabetic Conditions with Static Versus Dynamic Flow Environment—Impact on Aortic Valve Remodeling

“…Under dynamic flow cultivation, ACTA2 expression remained unchanged. However, unchanged ACTA2 expression by HG is in line with our previous observations in VIC in a 2D culture model [16] and it is further in line with reports from other groups on VIC in a gelatin methacrylate 3D model [24] and also on cardiac fibroblasts [25]. Unaltered ACTA2 expression in our bioreactor system might therefore be indicative for a balanced stress level.…”

“…To our knowledge, the impact of diabetes or diabetic conditions on insulin signaling pathways in 2D or 3D models of CAVD has not been described in the literature so far. However, studies for classical insulin signaling have been reported for cardiac fibroblasts [25] and cardiomyocytes [37,38]. Binding of insulin to the insulin receptor triggers a phosphorylation cascade of downstream proteins, whereby the insulin signal is transmitted intracellularly [12].…”

Glucolipotoxicity: A Proposed Etiology for Wooden Breast and Related Myopathies in Commercial Broiler Chickens

“…The greater role of insulinindependent glucose transport in cardiac and smooth muscle allows glucose uptake even when glycolysis and glycogenesis are impaired. The importance of insulin-insensitive glucose transport in development of diabetic retinopathy (Kumagai, 1999), atherosclerosis (Wall et al, 2018), diabetic nephropathy (Brosius and Heilig, 2005), pulmonary fibrosis (Cho et al, 2017), diabetic myocardial fibrosis (Asbun and Villarreal, 2006;Gorski et al, 2019) and non-alcoholic fatty liver disease (Nanji et al, 1995) has been demonstrated and is in support of our hypothesis that wooden breast shares substantial etiological factors with type 2 diabetes in mammals.…”

The Diabetic Cardiomyopathy: The Contributing Pathophysiological Mechanisms

“…The former is either mediated by angiotensin II activation or induced by high glucose and leptin via increasing transcription, secretion, and activation ( 169 , 262 , 263 ). On the other hand, in a study on a murine model of obesity and IR given a diabetogenic diet for 11 weeks, cardiac fibroblasts acquired enhanced myofibroblastic/fibrotic gene expression but reduced responsiveness to TGF-β1 ( 264 ). Similarly, cardiac fibroblasts isolated from db/db mice exhibited elevated collagen synthesis but weakened TGF-β1 response ( 256 ).…”