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Phospholipase C beta3 deficiency leads to macrophage hypersensitivity to apoptotic induction and reduction of atherosclerosis in mice.

ABSTRACT: Atherosclerosis is an inflammatory disease that is associated with monocyte recruitment and subsequent differentiation into lipid-laden macrophages at sites of arterial lesions, leading to the development of atherosclerotic plaques. PLC is a key member of signaling pathways initiated by G protein-coupled ligands in macrophages. However, the role of this enzyme in the regulation of macrophage function is not known. Here, we studied macrophages from mice lacking PLC beta2, PLC beta3, or both PLC isoforms and found that PLC beta3 is the major functional PLC beta isoform in murine macrophages. Although PLC beta3 deficiency did not affect macrophage migration, adhesion, or phagocytosis, it resulted in macrophage hypersensitivity to multiple inducers of apoptosis. PLC beta3 appeared to regulate this sensitivity via PKC-dependent upregulation of Bcl-XL. The significance of PLC beta signaling in vivo was examined using the apoE-deficient mouse model of atherosclerosis. Mice lacking both PLC beta3 and apoE exhibited fewer total macrophages and increased macrophage apoptosis in atherosclerotic lesions, as well as reduced atherosclerotic lesion size when compared with mice lacking only apoE. These results demonstrate what we believe to be a novel role for PLC activity in promoting macrophage survival in atherosclerotic plaques and identify PLC beta3 as a potential target for treatment of atherosclerosis.

SUBMITTER: Wang Z

PROVIDER: S-EPMC2129238 | biostudies-literature | 2008 Jan

REPOSITORIES: biostudies-literature

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Phospholipase C beta3 deficiency leads to macrophage hypersensitivity to apoptotic induction and reduction of atherosclerosis in mice.

Wang Zhenglong Z Liu Bei B Wang Ping P Dong Xuemei X Fernandez-Hernando Carlos C Li Zhong Z Hla Timothy T Li Zihai Z Claffey Kevin K Smith Jonathan D JD Wu Dianqing D

The Journal of clinical investigation 20080101 1

Atherosclerosis is an inflammatory disease that is associated with monocyte recruitment and subsequent differentiation into lipid-laden macrophages at sites of arterial lesions, leading to the development of atherosclerotic plaques. PLC is a key member of signaling pathways initiated by G protein-coupled ligands in macrophages. However, the role of this enzyme in the regulation of macrophage function is not known. Here, we studied macrophages from mice lacking PLC beta2, PLC beta3, or both PLC i ...[more]

PMID: 18079968

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Project description:Patients with diabetes mellitus can develop cardiac dysfunction in the absence of underlying coronary artery disease or hypertension; a condition defined as diabetic cardiomyopathy. Mice lacking the intracellular protein kinase Akt2 develop a syndrome that is similar to diabetes mellitus type 2. Expression profiling of akt2(-/-) myocardium revealed that Rab4a, a GTPase involved in glucose transporter 4 translocation and ?-adrenergic receptor (?AR) recycling to the plasma membrane, was significantly induced. We therefore hypothesized that Akt2 deficiency increases myocardial ?-adrenergic sensitivity. Confirmatory analysis revealed up-regulation of Rab4a mRNA and protein in akt2(-/-) myocardium. In cultured cardiomyocyte experiments, Rab4a was induced by pharmacological inhibition of Akt as well as by specific knockdown of Akt2 with siRNA. Isolated akt2(-/-) hearts were hypersensitive to isoproterenol (ISO) but exhibited normal sensitivity to forskolin. Prolonged ISO treatment led to increased cardiac hypertrophy in akt2(-/-) mice compared to wild type mice. In addition, spontaneous hypertrophy was noted in aged akt2(-/-) hearts that was inhibited by treatment with the ?AR blocker propranolol. In agreement with previous results demonstrating increased fatty acid oxidation rates in akt2(-/-) myocardium, we found increased peroxisome proliferator-activated receptor ? (PPAR?) activity in the hearts of these animals. Interestingly, increased myocardial Rab4a expression was present in mice with cardiac-specific overexpression of PPAR? and was also observed upon stimulation of PPAR? activity in cultured cardiomyocytes. Accordingly, propranolol attenuated the development of cardiac hypertrophy in the PPAR? transgenic mice as well. Our results indicate that reduced Akt2 leads to up-regulation of Rab4a expression in cardiomyocytes in a cell-autonomous fashion that may involve activation of PPAR?. This maladaptive response is associated with hypersensitivity of akt2(-/-) myocardium to ?-adrenergic stimulation.

Dataset Information

Phospholipase C beta3 deficiency leads to macrophage hypersensitivity to apoptotic induction and reduction of atherosclerosis in mice.

Publications

Phospholipase C beta3 deficiency leads to macrophage hypersensitivity to apoptotic induction and reduction of atherosclerosis in mice.

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