Cardiomyocyte Apoptosis Induced by Gαq Signaling Is Mediated by Permeability Transition Pore Formation and Activation of the Mitochondrial Death Pathway

• Published in: Circulation research Vol. 87; no. 12; pp. 1180 - 1187
• Main Authors: Adams, John W, Pagel, Amy L, Means, Christopher K, Oksenberg, Donna, Armstrong, Robert C, Heller Brown, Joan
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 08.12.2000; Lippincott
• Subjects: Biological and medical sciences; Fundamental and applied biological sciences. Psychology; Heart; Vertebrates: cardiovascular system; Heart; Rat; Rodentia; Smooth muscle; Heart ventricle; Permeability; Signal transduction; Vertebrata; Mitochondria; Mammalia; Cell death; Animal; Membrane pore; Circulatory system; Apoptosis; G protein
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.87.12.1180

ABSTRACT—Expression of the wild-type α subunit of Gq stimulates phospholipase C and induces hypertrophy in cardiomyocytes. Addition of Gq-coupled receptor agonists additionally activates phospholipase C, as does expression of a constitutively active mutant form of Gαq. Under these conditions, hypertrophy is rapidly succeeded by apoptotic cellular and molecular changes, including myofilament disorganization, loss of mitochondrial membrane potential, alterations in Bcl-2 family protein levels, DNA fragmentation, increased caspase activity (≈4-fold), cytochrome c redistribution, and nuclear chromatin condensation in ≈12% of the cells. We used various interventions to define the molecular relationships between these events and identify potential sites at which these features of apoptosis could be rescued. Treatment with caspase inhibitors prevented DNA fragmentation and promoted myocyte survival; however, cytochrome c release and loss of mitochondrial membrane potential still occurred. In contrast, treatment with bongkrekic acid, an inhibitor of the mitochondrial permeability transition pore, not only prevented DNA fragmentation and reduced nuclear chromatin condensation but also preserved mitochondrial membrane potential and limited cytochrome c redistribution to only ≈2% of cells. These data demonstrate the central role of mitochondrial membrane potential in initiation of caspase activation and downstream apoptotic events and suggest that preservation of mitochondrial integrity is crucial for prolonging the life and function of cardiomyocytes exposed to pathological levels of stress.