Apoptosis and heart failure: Mechanisms and therapeutic implications

Qin Chen, Victoria C. Tu

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

A large volume of experimental data supports the presence of apoptosis in failing hearts. Apoptosis in many types of cells results from exposure to cytotoxic cytokines or damaging agents. Cytotoxic cytokines such as tumor necrosis factor (TNF)-α or Fas ligand (FasL) bind to their receptors to activate caspase-8, while damaging agents can cause mitochondrial release of cytochrome c, which can initiate activation of caspase-9. Caspase-8 or -9 can activate a cascade of caspases. The p53 protein is often required for damaging agent-induced apoptosis. An imbalance of proapoptotic factors versus prosurvival factors in the bcl-2 family precedes the activation of caspases. Given these typical changes of apoptosis found in many cell types, the apoptotic pathway in cardiomyocytes is somewhat unconventional since in vivo experimental data reveal that apoptosis does not appear to be controlled by TNF-α, FasL, p53 or decrease of bcl-2. In vitro and in vivo studies suggest the importance of mitochondria and activation of caspases in cell death occurring in failing hearts. Oxidants, excessive nitric oxide, angiotensin II and catecholamines have been shown to trigger apoptotic death of cardiomyocytes. Eliminating these inducers reduces apoptosis and reverses the loss of contractile function in many cases, indicating the feasibility of the pharmacological application of antioxidants, nitric oxide synthetase inhibitors, ACE inhibitors, angiotensin II receptor antagonists and adrenergic receptor antagonists. Most inducers of apoptosis initiate a cascade of signaling events, including activation of the p38 mitogen-activated protein kinase. Small molecule inhibitors of p38 have been shown to be capable of preventing apoptosis and loss of contractile function associated with ischemia and reperfusion. Although further experimental work is needed, several studies have already indicated the beneficial effect of caspase inhibitors against cell loss and features of heart failure in vitro and in vivo. These studies indicate the importance of inhibiting apoptosis in therapeutic interventions against heart failure.

Original languageEnglish (US)
Pages (from-to)43-57
Number of pages15
JournalAmerican Journal of Cardiovascular Drugs
Volume2
Issue number1
StatePublished - 2002

Fingerprint

Heart Failure
Apoptosis
Caspases
Fas Ligand Protein
Therapeutics
Caspase 8
Cardiac Myocytes
Tumor Necrosis Factor-alpha
Cytokines
Adrenergic Antagonists
Caspase Inhibitors
Caspase 9
Angiotensin Receptor Antagonists
p38 Mitogen-Activated Protein Kinases
Cytochromes c
Angiotensin-Converting Enzyme Inhibitors
Oxidants
Nitric Oxide Synthase
Angiotensin II
Reperfusion

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology

Cite this

Apoptosis and heart failure : Mechanisms and therapeutic implications. / Chen, Qin; Tu, Victoria C.

In: American Journal of Cardiovascular Drugs, Vol. 2, No. 1, 2002, p. 43-57.

Research output: Contribution to journalArticle

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