Mitochondria‐localized caveolin in adaptation to cellular stress and injury

Fridolfsson, Heidi N.; Kawaraguchi, Yoshitaka; Ali, Sameh S.; Panneerselvam, Mathivadhani; Niesman, Ingrid R.; Finley, J. Cameron; Kellerhals, Sarah E; Migita, Michael Y.; Okada, Hideshi; Moreno, Ana M.; Jennings, Michelle; Kidd, Michael W.; Bonds, Jacqueline A.; Balijepalli, Ravi C.; Ross, Robert S.; Patel, Piyush M.; Miyanohara, Atsushi; Chen, Qun; Lesnefsky, Edward J.; Head, Brian P.; Roth, David M.; Insel, Paul A.; Patel, Hemal H.

doi:10.1096/fj.12-215798

Cited by 94 publications

(149 citation statements)

References 59 publications

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“…preconditioning (28). Increased expression of caveolin-3 in cardiac mitochondria was associated with enhanced respiratory function, reduced generation of ROS, and reduced infarct size during in vitro I/R (29). Conversely, caveolin-3 −/− mice show very low caveolar density (30) and are resistant to pharmacological preconditioning (31).…”

Section: Resultsmentioning

confidence: 95%

Targeted disruption of PDE3B, but not PDE3A, protects murine heart from ischemia/reperfusion injury

Chung

Lagranha

Chen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Although inhibition of cyclic nucleotide phosphodiesterase type 3 (PDE3) has been reported to protect rodent heart against ischemia/ reperfusion (I/R) injury, neither the specific PDE3 isoform involved nor the underlying mechanisms have been identified. Targeted disruption of PDE3 subfamily B (PDE3B), but not of PDE3 subfamily A (PDE3A), protected mouse heart from I/R injury in vivo and in vitro, with reduced infarct size and improved cardiac function. The cardioprotective effect in PDE3B −/− heart was reversed by blocking cAMP-dependent PKA and by paxilline, an inhibitor of mitochondrial calcium-activated K channels, the opening of which is potentiated by cAMP/PKA signaling. Compared with WT mitochondria, PDE3B−/− mitochondria were enriched in antiapoptotic Bcl-2, produced less reactive oxygen species, and more frequently contacted transverse tubules where PDE3B was localized with caveolin-3. Moreover, a PDE3B −/− mitochondrial fraction containing connexin-43 and caveolin-3 was more resistant to Ca 2+ -induced opening of the mitochondrial permeability transition pore. Proteomics analyses indicated that PDE3B−/− heart mitochondria fractions were enriched in buoyant ischemia-induced caveolin-3-enriched fractions (ICEFs) containing cardioprotective proteins. Accumulation of proteins into ICEFs was PKA dependent and was achieved by ischemic preconditioning or treatment of WT heart with the PDE3 inhibitor cilostamide. Taken together, these findings indicate that PDE3B deletion confers cardioprotective effects because of cAMP/PKA-induced preconditioning, which is associated with the accumulation of proteins with cardioprotective function in ICEFs. To our knowledge, our study is the first to define a role for PDE3B in cardioprotection against I/R injury and suggests PDE3B as a target for cardiovascular therapies. PDE3B−/− mice | protein kinase A | ischemia/reperfusion injury | signalosome | membrane repair

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Section: Resultsmentioning

confidence: 95%

Targeted disruption of PDE3B, but not PDE3A, protects murine heart from ischemia/reperfusion injury

Chung

Lagranha

Chen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…All data are presented as bar graphs and were analyzed using the GraphPad Prism 6 software (GraphPad Software, Inc.) as published previously (61). The data are depicted as mean ± SEM, and in all cases, P < 0.05 was considered statistically significant.…”

Section: Methodsmentioning

confidence: 99%

A kinase interacting protein (AKIP1) is a key regulator of cardiac stress

Sastri¹,

Haushalter²,

Panneerselvam

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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cAMP-dependent protein kinase (PKA) regulates a myriad of functions in the heart, including cardiac contractility, myocardial metabolism, and gene expression. However, a molecular integrator of the PKA response in the heart is unknown. Here, we show that the PKA adaptor A-kinase interacting protein 1 (AKIP1) is up-regulated in cardiac myocytes in response to oxidant stress. Mice with cardiac gene transfer of AKIP1 have enhanced protection to ischemic stress. We hypothesized that this adaptation to stress was mitochondrialdependent. AKIP1 interacted with the mitochondrial localized apoptosis inducing factor (AIF) under both normal and oxidant stress. When cardiac myocytes or whole hearts are exposed to oxidant and ischemic stress, levels of both AKIP1 and AIF were enhanced. AKIP1 is preferentially localized to interfibrillary mitochondria and up-regulated in this cardiac mitochondrial subpopulation on ischemic injury. Mitochondria isolated from AKIP1 genetransferred hearts showed increased mitochondrial localization of AKIP1, decreased reactive oxygen species generation, enhanced calcium tolerance, decreased mitochondrial cytochrome C release, and enhance phosphorylation of mitochondrial PKA substrates on ischemic stress. These observations highlight AKIP1 as a critical molecular regulator and a therapeutic control point for stress adaptation in the heart. ischemia/reperfusion | oxidative stress

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“…After each drug treatment, plasma membrane fluidity was determined by electron paramagnetic resonance (EPR) spin-labeling spectroscopy according to a previously published protocol (Fridolfsson et al 2012). Briefly, EPR identifies changes in the spin tropic movement of an unpaired electron.…”

Section: Plasma Membrane Fluidity Analysis By Electron Paramagnetic Rmentioning

confidence: 99%

Distinct pathways of cholesterol biosynthesis impact on insulin secretion

Zuniga-Hertz

Rebelato

Kassan

et al. 2014

Journal of Endocrinology

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Results from previous investigations have indicated that glucose-stimulated insulin secretion (GSIS) is affected by changes in cholesterol and its intermediates, but the precise link between secretion and cholesterol has not been thoroughly investigated. In this study, we show the contribution of both protein isoprenylation and cholesterol-dependent plasma membrane structural integrity to insulin secretion in INS-1E cells and mouse islets. Acute (2 h) inhibition of hydroxyl-methylglutaryl-CoA reductase by simvastatin (SIM) resulted in inhibition of GSIS without reduction in total cellular cholesterol content. This effect was prevented by cell loading with the isoprenyl molecule geranylgeranyl pyrophosphate. Chronic (24 h) inhibition of cholesterol biosynthesis resulted in inhibition of GSIS with a significant reduction in total cellular cholesterol content, which was also observed after the inhibition of cholesterol biosynthesis downstream of isoprenoid formation. Electron paramagnetic resonance analyses of INS-1E cells showed that the SIM-induced reduction in cholesterol increased plasma membrane fluidity. Thus, the blockade of cholesterol biosynthesis resulted in the reduction of availability of isoprenoids, followed by a reduction in the total cholesterol content associated with an increase in plasma membrane fluidity. Herein, we show the different contributions of cholesterol biosynthesis to GSIS, and propose that isoprenoid molecules and cholesterol-dependent signaling are dual regulators of proper b-cell function.

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Mitochondria‐localized caveolin in adaptation to cellular stress and injury

Cited by 94 publications

References 59 publications

Targeted disruption of PDE3B, but not PDE3A, protects murine heart from ischemia/reperfusion injury

Targeted disruption of PDE3B, but not PDE3A, protects murine heart from ischemia/reperfusion injury

A kinase interacting protein (AKIP1) is a key regulator of cardiac stress

Distinct pathways of cholesterol biosynthesis impact on insulin secretion

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