Caveolin-3 Overexpression Attenuates Cardiac Hypertrophy via Inhibition of T-type Ca2+ Current Modulated by Protein Kinase Cα in Cardiomyocytes

Markandeya, Yogananda S.; Phelan, Laura; Woon, Marites T.; Keefe, Alexis M.; Reynolds, Courtney; August, Benjamin K.; Hacker, Timothy A.; Roth, David M.; Patel, Hemal H.; Balijepalli, Ravi C.

doi:10.1074/jbc.m115.674945

Cited by 54 publications

(52 citation statements)

References 55 publications

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“…16, 21 Previous studies have demonstrated that the expression of caveolin-3 is decreased in different mouse and human cardiac diseases including heart failure and hypertrophy. 22–24 Loss of caveolin-3 is associated with redistribution of β 2 AR signal on the PM in failing myocytes. 25 Here, we reveal an 80% reduction of protein expression of caveolin-3 in the failing rabbit myocytes.…”

Section: Resultsmentioning

confidence: 99%

Genetically Encoded Biosensors Reveal PKA Hyperphosphorylation on the Myofilaments in Rabbit Heart Failure

Barbagallo

Reddy

et al. 2016

Circulation Research

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Rationale In heart failure, myofilament proteins display abnormal phosphorylation, which contributes to contractile dysfunction. The mechanisms underlying the dysregulation of protein phosphorylation on myofilaments is not clear. Objective This study aims to understand the mechanisms underlying altered phosphorylation of myofilament proteins in heart failure. Methods and Results We generate a novel genetically encoded protein kinase A (PKA) biosensor anchored onto the myofilaments in rabbit cardiac myocytes to examine PKA activity at the myofilaments in responses to adrenergic stimulation. We show that PKA activity is shifted from the sarcolemma to the myofilaments in hypertrophic failing rabbit myocytes. In particular, the increased PKA activity on the myofilaments is due to an enhanced β2 adrenergic receptor (β2AR) signal selectively directed to the myofilaments together with a reduced phosphodiesterase activity associated with the myofibrils. Mechanistically, the enhanced PKA activity on the myofilaments is associated with downregulation of caveolin-3 in the hypertrophic failing rabbit myocytes. Reintroduction of caveolin-3 in the failing myocytes is able to normalize the distribution of β2AR signal by preventing PKA signal access to the myofilaments, and to restore contractile response to adrenergic stimulation. Conclusions In hypertrophic rabbit myocytes, selectively enhanced β2AR signaling toward the myofilaments contributes to elevated PKA activity and PKA phosphorylation of myofilament proteins. Reintroduction of caveolin-3 is able to confine β2AR signaling and restore myocyte contractility in response to β-adrenergic stimulation.

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Section: Resultsmentioning

confidence: 99%

Genetically Encoded Biosensors Reveal PKA Hyperphosphorylation on the Myofilaments in Rabbit Heart Failure

Barbagallo

Reddy

et al. 2016

Circulation Research

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“…In contrast, adenoviral-mediated overexpression of Cav3 in isolated cardiomyocytes conferred protection from phenylephrineinduced hypertrophy (58), and transgenic mice with cardiomyocytespecific overexpression of Cav3 demonstrated attenuation of cardiac hypertrophy and preservation of function following TAC (15). This cardioprotection was attributed to increased natriuretic peptide expression, increased phosphorylation of Akt, and decreased NFAT nuclear translocation as a result of increased caveolae abundance (15,28). Similar to the protective signaling in Cav3 overexpression, we observed that Fgf13 KO up-regulated PI3K/Akt signaling and attenuated calcineurin/NFAT-mediated fetal gene reexpression after TAC (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…First, we hypothesized that Fgf13 KO would phenocopy Cav3 overexpression, which was shown to mitigate TAC-induced pathological remodeling in part by preventing disruption of caveolae-associated macromolecular signaling complexes otherwise seen after TAC (28). Second, based on recent studies in skeletal muscle and endothelial cells highlighting that caveolae can serve as mechanoprotective membrane reservoirs that buffer increases in membrane tension (29,30), we hypothesized that increased caveolae abundance in Fgf13 KO myocytes ameliorated membrane damage caused by TAC-induced mechanical stretch.…”

Section: Fgf13 Ko Increases Sarcolemmal Caveolae Density In Cardiacmentioning

confidence: 99%

Inducible Fgf13 ablation enhances caveolae-mediated cardioprotection during cardiac pressure overload

Wei

Sinden

Zhang

et al. 2017

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

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The fibroblast growth factor (FGF) homologous factor FGF13, a noncanonical FGF, has been best characterized as a voltage-gated Na + channel auxiliary subunit. Other cellular functions have been suggested, but not explored. In inducible, cardiac-specific Fgf13 knockout mice, we found-even in the context of the expected reduction in Na + channel current-an unanticipated protection from the maladaptive hypertrophic response to pressure overload. To uncover the underlying mechanisms, we searched for components of the FGF13 interactome in cardiomyocytes and discovered the complete set of the cavin family of caveolar coat proteins. Detailed biochemical investigations showed that FGF13 acts as a negative regulator of caveolae abundance in cardiomyocytes by controlling the relative distribution of cavin 1 between the sarcolemma and cytosol. In cardiac-specific Fgf13 knockout mice, cavin 1 redistribution to the sarcolemma stabilized the caveolar structural protein caveolin 3. The consequent increase in caveolae density afforded protection against pressure overload-induced cardiac dysfunction by two mechanisms: (i) enhancing cardioprotective signaling pathways enriched in caveolae, and (ii) increasing the caveolar membrane reserve available to buffer membrane tension. Thus, our results uncover unexpected roles for a FGF homologous factor and establish FGF13 as a regulator of caveolae-mediated mechanoprotection and adaptive hypertrophic signaling. (1), share a core domain with homology to canonical FGFs, but FHFs are not secreted, do not bind or activate FGF receptors, and do not function as growth factors (2). Instead, FHFs bind directly to voltage-gated Na + channels, modulating channel gating and trafficking (3, 4). Widely expressed in the brain (1), FHFs have been implicated in neurologic diseases such as spinocerebellar ataxia 27, caused by missense mutations in FGF14 that diminish Na + channel current, disrupt channel localization, and impair neuronal excitability (5-7).In addition to their broad distribution in the central nervous system, FHFs are expressed in the mammalian heart (1). Their roles in regulating cardiac function, however, have only been recently investigated. We showed that FGF13, the predominant FHF in rodent heart and a common transcript in human heart (8), directly binds to the C terminus of cardiac Na V 1.5 Na + channels, and thereby regulates current density and conduction velocity by affecting channel gating and surface expression (9). Similarly, mutations that disrupt interaction between Na V 1.5 and FGF12, the major human cardiac FHF, have been linked to lifethreatening arrhythmia syndromes (8, 10). In addition to regulating Na + channels, FHFs can modulate voltage-gated Ca 2+ channels (11, 12). Fgf13 knockdown in adult rodent ventricular cardiomyocytes decreased Ca V 1.2 current density, perturbed Ca V 1.2 localization at the dyad, and thereby affected Ca 2+ -induced Ca 2+ release (11). Because previous studies were conducted in cultured cardiomyocytes, however, the in vivo roles for FHFs in ...

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“…Others have shown that reduction of Cx43 and Na v 1.5 results in polymorphic ventricular arrhythmias in cardiac hypertrophy [16]. Interestingly, Cav-3 overexpression has been shown to protect against cardiac hypertrophic remodeling [20, 30]. …”

Section: Discussionmentioning

confidence: 99%

Electrophysiology and metabolism of caveolin-3-overexpressing mice

et al. 2016

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Caveolin-3 (Cav-3) plays a critical role in organizing signaling molecules and ion channels involved in cardiac conduction and metabolism. Mutations in Cav-3 are implicated in cardiac conduction abnormalities and myopathies. Additionally, cardiac specific overexpression of Cav-3 (Cav-3 OE) is protective against ischemic and hypertensive injury suggesting a potential role for Cav-3 in basal cardiac electrophysiology and metabolism involved in stress adaptation. We hypothesized that overexpression of Cav-3 may alter baseline cardiac conduction and metabolism. We examined: 1) ECG telemetry recordings at baseline and during pharmacological interventions, 2) ion channels involved in cardiac conduction with immunoblotting and computational modeling, and 3) baseline metabolism in Cav-3 OE and transgene negative littermate control mice. Cav-3 OE mice had decreased heart rates, prolonged PR intervals, and shortened QTc intervals with no difference in activity compared to control mice. Dobutamine or propranolol did not cause significant changes between experimental groups in maximal (dobutamine) or minimal (propranolol) heart rate. Cav-3 OE mice had an overall lower chronotropic response to atropine. Expression of Kv1.4 and Kv4.3 channels, Nav1.5 channels and connexin 43 were increased in Cav-3 OE mice. A computational model integrating the immunoblotting results indicated shortened action potential duration in Cav-3 OE mice linking the change in channel expression to the observed electrophysiology phenotype. Metabolic profiling showed no gross differences in VO2, VCO2, respiratory exchange ratio, and heat generation, feeding or drinking. In conclusion, Cav-3 OE mice have changes in ECG intervals, heart rates, and cardiac ion channel expression. These findings give novel mechanistic insights into previously reported Cav-3 dependent cardioprotection.

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Caveolin-3 Overexpression Attenuates Cardiac Hypertrophy via Inhibition of T-type Ca2+ Current Modulated by Protein Kinase Cα in Cardiomyocytes

Cited by 54 publications

References 55 publications

Genetically Encoded Biosensors Reveal PKA Hyperphosphorylation on the Myofilaments in Rabbit Heart Failure

Genetically Encoded Biosensors Reveal PKA Hyperphosphorylation on the Myofilaments in Rabbit Heart Failure

Inducible Fgf13 ablation enhances caveolae-mediated cardioprotection during cardiac pressure overload

Electrophysiology and metabolism of caveolin-3-overexpressing mice

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