• Namrita Kaur

Student thesis: Phd


Heart failure (HF) associated with diabetes is a distinct clinical entity known as diabetic cardiomyopathy (DCM) without the prevalence of other risk factors such as hypertension. The human heart is a pool of different cell types, including cardiomyocytes, fibroblasts, endothelial cells and immune cells, interacting via various secretory factors. The cardiomyocyte acting as an active mediator of the inflammatory response is an emerging concept with limited mechanistic understanding. Superimposed effects of hyperglycaemia and hyperlipidaemia dysregulate the intercellular links, contributing to diabetes-induced cardiac dysfunction. DCM is instigated by various pathological insults, including endoplasmic reticulum (ER) stress response and ectopic fibroblast growth factor receptor 1 (FGFR1) signalling, resulting in detrimental impacts on cardiac structure and function. Hence, elucidating the paracrine and autocrine mediators of cardiac intracellular signalling can provide new mechanistic and therapeutic strategies for HF in diabetes. First, we demonstrate the opposing roles of the cardiac ER stress response in our time-course model of high fat high-sugar diet (HFHSD)-induced diabetes. Using cardiac P21-activated kinase 2 (PAK2) deficient mice, we found that PAK2, an ER-localised signalling kinase, decelerates the transition from an adaptive to a maladaptive ER response in DCM. A concurrent examination of the myocardial inflammation, particularly macrophage response, revealed chronic cardiac ER stress to be the initiating cascade of the alarmin high-mobility group box 1 (HMGB1) in DCM. HMGB1 expression and subsequent secretion into the circulation was promoted via C/EBP homologous protein (CHOP), an ER stress responder. Our in vivo DCM models of ER dysfunction, the remediated ER response and pharmacological treatments established the functional and therapeutic relevance of targeting cardiac ER stress-mediated inflammation for alleviating DM-induced cardiac complications. Secondly, we determined that the FGFR1 cascade is the upstream facilitator of the PAK2 response. In diabetes, we observed a lack of cardiac FGFR1 and beta-Klotho (β-KL) signalling. We found that restoring cardiac FGFR1/β-KL expression results in the increased secretion of anti-inflammatory and proangiogenic factors from cardiomyocytes. Using proteomic analyses, we identified key cardiac-derived signals that regulate angiogenesis and macrophage polarisation upon FGFR1/β-KL activation in diabetes. This provides a proof-of-concept to explore the novel therapeutic avenue of myocardial cell interactions to prevent cardiac dysfunction under metabolic stress. Type 2 diabetes is a chronic disorder; therefore, our time-course analyses provide a fascinating insight into the early mechanistic events in DCM. We address the knowledge gap of cardiomyocyte-mediated macrophage and endothelial cell response and reveal mechanistic links behind cardiac inflammation and vascular damage in response to diet-induced metabolic stress. Hence, further dissection of the identified molecular web between cardiomyocytes and endothelial cells or macrophages in DCM may lead to the development of efficacious treatments for diabetes-induced HF.
Date of Award1 Aug 2023
Original languageEnglish
Awarding Institution
  • The University of Manchester
SupervisorEileithyia Swanton (Supervisor) & Wei Liu (Supervisor)


  • Diabetes
  • signal transduction
  • ER stress
  • angiogenesis
  • diastolic dysfunction
  • PAK2
  • paracrine effect
  • inflammation
  • intercellular communication
  • heart failure
  • diabetic cardiomyopathy
  • FGFR1

Cite this