Obesity, metabolic dysfunction, and cardiac fibrosis

Pathophysiological pathways, molecular mechanisms, and therapeutic opportunities

Michele Cavalera, Junhong Wang, Nikolaos G. Frangogiannis

Research output: Contribution to journalArticle

92 Citations (Scopus)

Abstract

Cardiac fibrosis is strongly associated with obesity and metabolic dysfunction and may contribute to the increased incidence of heart failure, atrial arrhythmias, and sudden cardiac death in obese subjects. This review discusses the evidence linking obesity and myocardial fibrosis in animal models and human patients, focusing on the fundamental pathophysiological alterations that may trigger fibrogenic signaling, the cellular effectors of fibrosis, and the molecular signals that may regulate the fibrotic response. Obesity is associated with a wide range of pathophysiological alterations (such as pressure and volume overload, metabolic dysregulation, neurohumoral activation, and systemic inflammation); their relative role in mediating cardiac fibrosis is poorly defined. Activation of fibroblasts likely plays a major role in obesity-associated fibrosis; however, inflammatory cells, cardiomyocytes, and vascular cells may also contribute to fibrogenic signaling. Several molecular processes have been implicated in regulation of the fibrotic response in obesity. Activation of the renin-angiotensin-aldosterone system, induction of transforming growth factor β, oxidative stress, advanced glycation end-products, endothelin 1, Rho-kinase signaling, leptin-mediated actions, and upregulation of matricellular proteins (such as thrombospondin 1) may play a role in the development of fibrosis in models of obesity and metabolic dysfunction. Moreover, experimental evidence suggests that obesity and insulin resistance profoundly affect the fibrotic and remodeling response after cardiac injury. Understanding the pathways implicated in obesity-associated fibrosis may lead to the development of novel therapies to prevent heart failure and attenuate postinfarction cardiac remodeling in patients with obesity.

Original languageEnglish (US)
Pages (from-to)323-335
Number of pages13
JournalTranslational Research
Volume164
Issue number4
DOIs
StatePublished - Oct 1 2014

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Fibrosis
Obesity
Chemical activation
Thrombospondin 1
rho-Associated Kinases
Advanced Glycosylation End Products
Oxidative stress
Angiotensins
Transforming Growth Factors
Endothelin-1
Fibroblasts
Leptin
Aldosterone
Renin
Animals
Therapeutics
Insulin
Heart Failure
Proteins
Sudden Cardiac Death

Keywords

  • (PAI)-1 = Plasminogen activator inhibitor-1
  • (PPAR)-α = Peroxisome proliferator-activated receptor-α
  • (TGF)-β1 = Transforming Growth Factor-β1
  • (TSP)-1 = Thrombospondin-1
  • ACE = Angiotensin converting enzyme
  • AGEs = Advanced glycation end-products
  • AT1 = Angiotensin type 1
  • BMI = Body-mass index
  • EndMT = Endothelial-mesenchymal transition
  • ET-1 = Endothelin-1
  • MMP = Matrix metalloproteinase
  • RAAS = Renin-angiotensin-aldosterone system
  • RAGEs = Receptor for advanced glycation end-products
  • RhoA = Ras homolog gene family member A
  • ROCK = Rho-kinase
  • ROS = Reactive oxygen species
  • WT = Wildtype
  • α-SMA = α-smooth muscle actin

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, medical
  • Public Health, Environmental and Occupational Health

Cite this

Obesity, metabolic dysfunction, and cardiac fibrosis : Pathophysiological pathways, molecular mechanisms, and therapeutic opportunities. / Cavalera, Michele; Wang, Junhong; Frangogiannis, Nikolaos G.

In: Translational Research, Vol. 164, No. 4, 01.10.2014, p. 323-335.

Research output: Contribution to journalArticle

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N2 - Cardiac fibrosis is strongly associated with obesity and metabolic dysfunction and may contribute to the increased incidence of heart failure, atrial arrhythmias, and sudden cardiac death in obese subjects. This review discusses the evidence linking obesity and myocardial fibrosis in animal models and human patients, focusing on the fundamental pathophysiological alterations that may trigger fibrogenic signaling, the cellular effectors of fibrosis, and the molecular signals that may regulate the fibrotic response. Obesity is associated with a wide range of pathophysiological alterations (such as pressure and volume overload, metabolic dysregulation, neurohumoral activation, and systemic inflammation); their relative role in mediating cardiac fibrosis is poorly defined. Activation of fibroblasts likely plays a major role in obesity-associated fibrosis; however, inflammatory cells, cardiomyocytes, and vascular cells may also contribute to fibrogenic signaling. Several molecular processes have been implicated in regulation of the fibrotic response in obesity. Activation of the renin-angiotensin-aldosterone system, induction of transforming growth factor β, oxidative stress, advanced glycation end-products, endothelin 1, Rho-kinase signaling, leptin-mediated actions, and upregulation of matricellular proteins (such as thrombospondin 1) may play a role in the development of fibrosis in models of obesity and metabolic dysfunction. Moreover, experimental evidence suggests that obesity and insulin resistance profoundly affect the fibrotic and remodeling response after cardiac injury. Understanding the pathways implicated in obesity-associated fibrosis may lead to the development of novel therapies to prevent heart failure and attenuate postinfarction cardiac remodeling in patients with obesity.

AB - Cardiac fibrosis is strongly associated with obesity and metabolic dysfunction and may contribute to the increased incidence of heart failure, atrial arrhythmias, and sudden cardiac death in obese subjects. This review discusses the evidence linking obesity and myocardial fibrosis in animal models and human patients, focusing on the fundamental pathophysiological alterations that may trigger fibrogenic signaling, the cellular effectors of fibrosis, and the molecular signals that may regulate the fibrotic response. Obesity is associated with a wide range of pathophysiological alterations (such as pressure and volume overload, metabolic dysregulation, neurohumoral activation, and systemic inflammation); their relative role in mediating cardiac fibrosis is poorly defined. Activation of fibroblasts likely plays a major role in obesity-associated fibrosis; however, inflammatory cells, cardiomyocytes, and vascular cells may also contribute to fibrogenic signaling. Several molecular processes have been implicated in regulation of the fibrotic response in obesity. Activation of the renin-angiotensin-aldosterone system, induction of transforming growth factor β, oxidative stress, advanced glycation end-products, endothelin 1, Rho-kinase signaling, leptin-mediated actions, and upregulation of matricellular proteins (such as thrombospondin 1) may play a role in the development of fibrosis in models of obesity and metabolic dysfunction. Moreover, experimental evidence suggests that obesity and insulin resistance profoundly affect the fibrotic and remodeling response after cardiac injury. Understanding the pathways implicated in obesity-associated fibrosis may lead to the development of novel therapies to prevent heart failure and attenuate postinfarction cardiac remodeling in patients with obesity.

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KW - ACE = Angiotensin converting enzyme

KW - AGEs = Advanced glycation end-products

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KW - MMP = Matrix metalloproteinase

KW - RAAS = Renin-angiotensin-aldosterone system

KW - RAGEs = Receptor for advanced glycation end-products

KW - RhoA = Ras homolog gene family member A

KW - ROCK = Rho-kinase

KW - ROS = Reactive oxygen species

KW - WT = Wildtype

KW - α-SMA = α-smooth muscle actin

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