Cavin-2 loss exacerbates hypoxia-induced pulmonary hypertension with excessive eNOS phosphorylation and protein nitration.

Pulmonary hypertension (PH) is associated with a poor prognosis even in recent years. Caveolin-1 (CAV1), a caveolae-associated protein, is a causal gene in PH. Cavin-2, one of the other caveolae-associated proteins, forms protein complexes with CAV1 and influences each other's functions. However, the role of Cavin-2 in PH has not been thoroughly investigated. To clarify the role of Cavin-2 in PH, we exposed Cavin-2-deficient (Cavin-2 KO) mice to hypoxia. A part of the analyses was confirmed in human pulmonary endothelial cells (HPAECs). After 4-week 10% O2 hypoxic exposure, we performed physiological, histological, and immunoblotting analyses. Right ventricular (RV) systolic pressure elevation and RV hypertrophy were exacerbated in Cavin-2 KO mice with hypoxia-induced PH (Cavin-2 KO PH mice). The vascular wall thickness of pulmonary arterioles was aggravated in Cavin-2 KO PH mice. Cavin-2 loss reduced CAV1 and induced sustained endothelial nitric oxide synthase (eNOS) hyperphosphorylation in the Cavin-2 KO PH lungs and HPAECs. NOx production associated with eNOS phosphorylation was also increased in the Cavin-2 KO PH lung and HPAECs. Furthermore, the nitration of proteins, including protein kinase G (PKG), was raised in the Cavin-2 KO PH lungs. In conclusion, we revealed that Cavin-2 loss exacerbated hypoxia-induced PH. Our results suggest that Cavin-2 loss leads to sustained eNOS hyperphosphorylation in pulmonary artery endothelial cells via CAV1 reduction, resulting in Nox overproduction-mediated nitration of proteins, including PKG, in smooth muscle cells.

Association of initial prednisolone dose with remission, relapse, and infectious complications in adult-onset minimal change disease.

BACKGROUND: A dose of 0.5-1 mg/kg/day of prednisolone (PSL) is administered for the initial treatment of minimal change disease (MCD). However, little is known about the optimal PSL dose for the initial treatment of MCD. METHODS: We conducted a retrospective multicenter cohort study of treatment-naive adult patients with MCD diagnosed by renal biopsy from 1981 to 2015 in whom PSL monotherapy was performed as the initial treatment. The exposure of interest was an initial median PSL dose of < 0.63 mg/kg/day (Group L) compared to ≥ 0.63 mg/kg/day (Group H). Cumulative remission and relapse after remission were compared between these groups using Cox regression adjusted for baseline characteristics. RESULTS: Ninety-one patients met the inclusion criteria. During a median follow-up of 2.98 years, 87 (95.6%) patients achieved complete remission, and 47.1% relapsed after remission. There was no significant difference in the remission rate between the groups at 4 weeks of follow-up (66.7 vs. 82.6%). The median time to remission in Group L was comparable to that in Group H (17.0 vs. 14.0 days). A multivariable Cox hazard model revealed that the initial PSL dose was not a significant predictor of remission. The cumulative steroid doses at 6 months, 1 year, and 2 years after treatment initiation were significantly lower in Group L than in Group H. CONCLUSION: The initial PSL dose was not associated with time to remission, remission rate, time to relapse, or relapse rate. Therefore, a low initial steroid dose may be sufficient to achieve remission.

Reduced Plasma Ascorbate and Increased Proportion of Dehydroascorbic Acid Levels in Patients Undergoing Hemodialysis.

Ascorbate functions as an electron donor and scavenges free radicals. Dehydroascorbic acid (DHA), the oxidized form of ascorbate, is generated as a result of these reactions. While low plasma ascorbate levels have been reported in hemodialysis patients worldwide, no studies have measured DHA because it is not generalized. In this study, we aimed to clarify whether plasma ascorbate levels are low in dialysis patients and whether plasma ascorbate levels fluctuate before and after dialysis. Moreover, we applied our previously established method to measure the plasma ascorbate and DHA levels in chronic kidney disease (CKD) stage G3-G5 non-hemodialysis-dependent patients, and pre- and post-dialysis plasma ascorbate and DHA levels in CKD stage G5D hemodialysis patients. The sample size was calculated using G-power software. The pre-dialysis plasma total ascorbate levels, including DHA, were significantly (56%) lower in hemodialysis patients than in non-hemodialysis-dependent CKD patients. After dialysis, there was a 40% reduction in the plasma total ascorbate levels. Hemodialysis increased the post-dialysis plasma proportions of DHA from 37% to 55%. The study results demonstrated lower plasma total ascorbate levels in hemodialysis patients compared with in non-hemodialysis-dependent CKD patients; these low levels in hemodialysis patients were further reduced by hemodialysis and increased DHA proportion.

A retrospective analysis of treatment outcomes in 45 patients with cardiac light-chain amyloidosis: a single-center experience in Japan.

The prognosis of cardiac light-chain (AL) amyloidosis is considered to be very poor. We studied the treatment efficacy and outcomes by retrospectively analyzing the clinical results of 45 patients with cardiac AL amyloidosis treated at our hospital between September 2008 and March 2016. The group of patients analyzed included 29 males and 16 females with a median age of 68 years. Their baseline median NT-proBNP, cTnT, and dFLC were 3167 pg/ml, 0.080 ng/ml, and 286.17 mg/l, respectively. Twenty-eight patients were in Cardiac Stage (CS) III and 17 patients were in Revised Prognostic Stage (RPS) IV. At the median follow-up of 10 months, the median overall survival (OS) was 16 months and 3-year OS was 35.9%. The patients in CS III showed significantly poorer survival rate than those in CS I or II (3-year OS: 12.2% vs. 65.8%, p = 0.0115) and the patients in RPS IV showed significantly poorer survival rate than those in RPS I, II, or III (3-year OS: 11.0% vs. 53.3%, p = 0.000914). Regardless of the therapeutic approaches, patients who achieved hematological CR or cardiac organ response demonstrated significantly improved prognosis. Therefore, achievement of hematological and organ responses is important in the treatment of cardiac AL amyloidosis.

Gut microbiota differences in elderly subjects between rural city Kyotango and urban city Kyoto: an age-gender-matched study.

Several outcomes have been reported on the role of gut microbiota in health promotion and disease prevention. Kyotango, one of the longevity areas with various centenarians, is a provincial city located in the northern part of Kyoto Prefecture in Japan. To understand the relationship between gut microbiota and urbanization, we compared the diversity, abundance, and function of gut microbiota in older healthy subjects between Kyotango and Kyoto cities; Kyoto is an urban city located in the southern part of Kyoto Prefecture. In total, 51 subjects at Kyotango and 51 subjects at Kyoto matched by age and gender were recruited, and their fecal samples were obtained to analyze the gut microbiota using 16S rRNA gene sequencing. Principal coordinate analysis for ß-diversity revealed significant differences in the gut microbiota between two cities. In contrast, the analysis of α-diversity revealed no significant differences between the groups. On comparison at the phylum levels, the abundance of Firmicutes was decreased with the urbanization, whereas that of Proteobacteria and Bacteroidetes increased. On comparison at the genus levels, with urbanization, a significant decrease was observed in Lachnospiraceae families including genus Roseburia and Coprococcus, and significant increases was observed in Bacteroides, Oscillospira, Parabacteroides, and Ruminococcus. The most markedly increased functional pathway with urbanization was lipopolysaccharide biosynthesis proteins and lipopolysaccharide biosynthesis, and decreased pathway was transporters and ABC transporters. In conclusion, the present findings indicate significant differences in the gut microbiota between the provincial city and urban cities at Kyoto Prefecture. These alterations in the microbiota may provide new insights to consider the relationship between longevity and gut microbiota.

Vasculitis and crescentic glomerulonephritis in a newly established congenic mouse strain derived from ANCA-associated vasculitis-prone SCG/Kj mice.

Lupus nephritis (LN) is the secondary glomerulonephritis (GN) involved in systemic lupus erythematosus (SLE) and a typical immune complex-type GN. Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is an autoimmune disease characterized by systemic vasculitis and pauci-immune-type crescentic glomerulonephritis (CrGN) with ANCA production. Human AAV causes death due to lung haemorrhage and end-stage renal disease, for which renal replacement therapies are necessary. The SLE/AAV overlap syndrome was recently reported in humans. The spontaneous crescentic glomerulonephritis-forming/Kinjoh (SCG/Kj) mouse is a unique model of human AAV showing production of myeloperoxidase (MPO)-ANCA. We previously discovered seven disease susceptibility quantitative trait loci (QTL) derived from SCG/Kj mice by linkage analysis. To investigate the individual functions of each QTL, and to identify AAV susceptibility genes, we introduced them into a B6/lpr background to establish SCG/Kj interval congenic mice (SICM). B6/lpr.C1scg mice, a type of SICM, exhibited the production of autoantibodies, including MPO-ANCA. The GN in B6/lpr.C1scg mice was not pauci-immune type: deposition of immunoglobulins and complement components was observed in nephritic glomeruli, similar to that in LN. The incidence of GN in female B6/lpr.C1scg mice was 100%. Granulocyte infiltration was also observed in the glomerular tuft and crescents. B6/lpr.C1scg mice also displayed vasculitis in multiple organs, most frequently the lung and kidney. Vasculitis was characterized by the infiltration of mononuclear cells to vascular walls followed by granulocyte infiltration, resembling human lupus vasculitis. The incidence of lung vasculitis was over 90% in male and female B6/lpr.C1scg mice. Blood MPO-ANCA levels were significantly associated with histopathological disease phenotypes. MPO deposition was observed in nephritic glomeruli, and granulocytes infiltrated into inflamed vessels and glomeruli. These observations suggest that the activation of granulocytes and local MPO release contribute to the pathogenesis of GN and vasculitis. As a monocongenic mouse, B6/lpr.C1scg mice show the association between murine chromosome 1 segment and autoimmunity. This strain can be used as a model of the SLE/AAV overlap syndrome, and will be useful for elucidating the mechanism of ANCA generation and the pathogenesis of CrGN and vasculitis, as well as in the search for genetic factors related to AAV.

A Purified, Solvent-Intercalated Precursor Complex for Wide-Process-Window Fabrication of Efficient Perovskite Solar Cells and Modules.

A high-purity methylammonium lead iodide complex with intercalated dimethylformamide (DMF) molecules, CH3 NH3 PbI3 ⋅DMF, is introduced as an effective precursor material for fabricating high-quality solution-processed perovskite layers. Spin-coated films of the solvent-intercalated complex dissolved in pure dimethyl sulfoxide (DMSO) yielded thick, dense perovskite layers after thermal annealing. The low volatility of the pure DMSO solvent extended the allowable time for low-speed spin programs and considerably relaxed the precision needed for the antisolvent addition step. An optimized, reliable fabrication method was devised to take advantage of this extended process window and resulted in highly consistent performance of perovskite solar cell devices, with up to 19.8 % power-conversion efficiency (PCE). The optimized method was also used to fabricate a 22.0 cm2 , eight-cell module with 14.2 % PCE (active area) and 8.64 V output (1.08 V/cell).

Senescence marker protein 30 protects intestinal epithelial cells against inflammation-induced cell death by enhancing Nrf2 activity.

Senescence marker protein 30 (SMP30) is a calcium-binding protein whose expression decreases during senescence. SMP30 deficiency increases susceptibility to cytokine-induced apoptosis in the liver and to radiation-induced apoptosis in the small intestine. Furthermore, colonic epithelial cell death is associated with the severity of colitis. Therefore, in the present study, we investigated the function of SMP30 during intestinal inflammation. In SMP30 deficient mice, colitis was significantly exacerbated as demonstrated by increased mortality (p = 0.001), body weight loss (p = 0.0105 at day 8), rectal bleeding (p = 0.0047 at day 8) and diarrhea (p = 0.0030 at day 8), histological scores (ulcers, p = 0.0002; edema, p = 0.0125; leukocyte infiltration, p = 0.0016) and productions of pro-inflammatory cytokines (IL-1α, p = 0.0452; IL-6, p = 0.0074; G-CSF, p = 0.0036). In addition, greater proportions of apoptotic cells and lower levels of anti-apoptotic marker proteins (total PARP-1 and Bcl-2) were observed in the inflamed intestines of SMP30 deficient mice than in wild type controls. In vitro experiments on colonic epithelial cells showed that stable SMP30 expression inhibited but that SMP30 siRNA expression increased TNF-α-induced apoptosis. SMP30 inhibition decreased Nrf2 mRNA expression levels (p < 0.0001), but SMP30 overexpression increased Nrf2 mRNA expression levels (p = 0.0495). The underlying mechanism by which SMP30 protected cells appeared to be by inhibiting Nrf2 ubiquitination and Keap1 expression, and thus enhancing Nrf2 activity. Moreover, SMP30 deficiency increased the incidence of colitis-associated colon cancer as determined by increased mortality (p = 0.0572) and average polyp number (p = 0.0277). Collectively, these findings suggest that SMP30 protects intestinal epithelial cells from apoptosis and this can contribute to amelioration of colitis and colitis-associated colon cancer.

Loss of MURC/Cavin-4 induces JNK and MMP-9 activity enhancement in vascular smooth muscle cells and exacerbates abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is relatively common in elderly patients with atherosclerosis. MURC (muscle-restricted coiled-coil protein)/Cavin-4 modulating the caveolae function of muscle cells is expressed in cardiomyocytes, skeletal muscle cells and smooth muscle cells. Here, we show a novel functional role of MURC/Cavin-4 in vascular smooth muscle cells (VSMCs) and AAA development. Both wild-type (WT) and MURC/Cavin-4 knockout (MURC-/-) mice subjected to periaortic application of CaCl2 developed AAAs. Six weeks after CaCl2 treatment, internal and external aortic diameters were significantly increased in MURC-/- AAAs compared with WT AAAs, which were accompanied by advanced fibrosis in the tunica media of MURC-/- AAAs. The activity of JNK and matrix metalloproteinase (MMP) -2 and -9 were increased in MURC-/- AAAs compared with WT AAAs at 5 days after CaCl2 treatment. At 6 weeks after CaCl2 treatment, MURC-/- AAAs exhibited attenuated JNK activity compared with WT AAAs. There was no difference in the activity of MMP-2 or -9 between saline and CaCl2 treatments. In MURC/Cavin-4-knockdown VSMCs, TNFα-induced activity of JNK and MMP-9 was enhanced compared with control VSMCs. Furthermore, WT, MURC-/-, apolipoprotein E-/- (ApoE-/-), and MURC/Cavin-4 and ApoE double-knockout (MURC-/-ApoE-/-) mice were subjected to angiotensin II (Ang II) infusion. In both ApoE-/- and MURC-/-ApoE-/- mice infused for 4 weeks with Ang II, AAAs were promoted. The internal aortic diameter was significantly increased in Ang II-infused MURC-/-ApoE-/- mice compared with Ang II-infused ApoE-/- mice. In MURC/Cavin-4-knockdown VSMCs, Ang II-induced activity of JNK and MMP-9 was enhanced compared with control VSMCs. Our results suggest that MURC/Cavin-4 in VSMCs modulates AAA progression at the early stage via the activation of JNK and MMP-9. MURC/Cavin-4 is a potential therapeutic target against AAA progression.

Orbicularis oculi muscle tightening for involutional entropion.

AIMS: To describe a novel technique for involutional entropion (IE) correction and present a retrospective case study. PATIENTS AND METHODS: The entropion eyelid was corrected by repairing the thin preseptal orbicularis oculi muscle (OOM) of the lower eyelid. Patients underwent correction with this method from 2005 to 2014 and were followed up for 2 years postoperatively. They were evaluated retrospectively with chart review (operation time, recurrence rate, operator years of experience as a plastic surgeon, etc.). Risk factors for recurrence were analyzed. RESULTS: Fifty-six patients (70 eyelids) were evaluated. The mean operation time was 37.6 min. Postoperative ectropion (over-correction) was observed in 1 patient (1.4%); a local skin flap was performed for this patient. There was recurrence of entropion in 4 patients (5.7%). These 4 patients with recurrent entropion underwent repeat surgery with the same method and achieved good eyelid position. No risk factors were found in this study. CONCLUSION: We consider IE to be mainly caused by the protrusion of orbital fat. The aim of this procedure was to reduce the orbital fat protrusion with OOM tightening. Advantages of this method are that it is technically easy, it is minimally invasive, operative times are short, recurrence rates are low, and esthetic outcomes are good.

Photocyclization of photoswitches with high enantioselectivity in human serum albumin in an artificial environment.

Three photochromic bisthienylethenes exhibited 56 to >99% enantiomeric excess in photochemical ring closure upon UV irradiation when incorporated in human serum albumin dissolved in 15% acetonitrile-phosphate buffer solution and incubated for 24 h at -4 °C. The absolute stereochemistry of the major enantiomers of two bisthienylethenes has been determined by their chemical transformations.

Usefulness of peripheral arterial signs in the evaluation of aortic regurgitation.

BACKGROUND: Early diagnosis and optimal timing of surgical repair for chronic aortic regurgitation (AR) are topics of interest, because left ventricular compensation delays the clinical signs of the early stages of left ventricular dysfunction. Various physical signs have been described as indicators of chronic AR, but AR screening can be difficult depending on the proficiency of primary care providers. The recent use of the cardio-ankle vascular index (CAVI) measurement to assess peripheral atherosclerosis may detect AR objectively and simply because its arterial pulse wave configuration is closely related to the physical signs of AR. METHODS: CAVI measurements include pulse pressure (PP), the difference in blood pressures between upper and lower limbs (ABD), ankle-brachial index (ABI), ejection time (ET), and upstroke time (UT). We evaluated the differences in CAVI parameters between AR group and age-matched control group, the relationships between CAVI parameters and the echocardiographic semi-quantitative measurements of AR severity such as left ventricular dimensions (Dd, Ds) and vena contracta (VC), and between the changes in CAVI parameters before and after aortic valve replacement. RESULTS: ABD, PP, ET, ankle systolic pressure and ABI in the AR group were significantly higher than that in the control group. Brachial diastolic pressure and CAVI in the AR group were significantly lower than that in the control group. UT was lower than that in the control group (p=0.05). PP did not correlate with the semi-quantitative AR severity, but ABD was correlated with Dd, Ds, and VC and was negatively correlated with UT. The exaggerated ABD, PP, ET, and ABI were moderated after surgery. CONCLUSIONS: CAVI parameters could be useful in the screening and serial follow-up of AR patients.

PTRF/Cavin-1 Deficiency Causes Cardiac Dysfunction Accompanied by Cardiomyocyte Hypertrophy and Cardiac Fibrosis.

Mutations in the PTRF/Cavin-1 gene cause congenital generalized lipodystrophy type 4 (CGL4) associated with myopathy. Additionally, long-QT syndrome and fatal cardiac arrhythmia are observed in patients with CGL4 who have homozygous PTRF/Cavin-1 mutations. PTRF/Cavin-1 deficiency shows reductions of caveolae and caveolin-3 (Cav3) protein expression in skeletal muscle, and Cav3 deficiency in the heart causes cardiac hypertrophy with loss of caveolae. However, it remains unknown how loss of PTRF/Cavin-1 affects cardiac morphology and function. Here, we present a characterization of the hearts of PTRF/Cavin-1-null (PTRF-/-) mice. Electron microscopy revealed the reduction of caveolae in cardiomyocytes of PTRF-/- mice. PTRF-/- mice at 16 weeks of age developed a progressive cardiomyopathic phenotype with wall thickening of left ventricles and reduced fractional shortening evaluated by echocardiography. Electrocardiography revealed that PTRF-/- mice at 24 weeks of age had low voltages and wide QRS complexes in limb leads. Histological analysis showed cardiomyocyte hypertrophy accompanied by progressive interstitial/perivascular fibrosis. Hypertrophy-related fetal gene expression was also induced in PTRF-/- hearts. Western blotting analysis and quantitative RT-PCR revealed that Cav3 expression was suppressed in PTRF-/- hearts compared with that in wild-type (WT) ones. ERK1/2 was activated in PTRF-/- hearts compared with that in WT ones. These results suggest that loss of PTRF/Cavin-1 protein expression is sufficient to induce a molecular program leading to cardiomyocyte hypertrophy and cardiomyopathy, which is partly attributable to Cav3 reduction in the heart.

MURC deficiency in smooth muscle attenuates pulmonary hypertension.

Emerging evidence suggests that caveolin-1 (Cav1) is associated with pulmonary arterial hypertension. MURC (also called Cavin-4) is a member of the cavin family, which regulates caveolar formation and functions together with caveolins. Here, we show that hypoxia increased Murc mRNA expression in the mouse lung, and that Murc-null mice exhibited attenuation of hypoxia-induced pulmonary hypertension (PH) accompanied by reduced ROCK activity in the lung. Conditional knockout mice lacking Murc in smooth muscle also resist hypoxia-induced PH. MURC regulates the proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) through Rho/ROCK signalling. Cav1 suppresses RhoA activity in PASMCs, which is reversed by MURC. MURC binds to Cav1 and inhibits the association of Cav1 with the active form of Gα13, resulting in the facilitated association of the active form of Gα13 with p115RhoGEF. These results reveal that MURC has a function in the development of PH through modulating Rho/ROCK signalling.

Free Carriers versus Excitons in CH3NH3PbI3 Perovskite Thin Films at Low Temperatures: Charge Transfer from the Orthorhombic Phase to the Tetragonal Phase.

We have investigated the dynamic optical properties of CH3NH3PbI3 (MAPbI3) perovskite thin films at low temperatures using time-resolved photoluminescence, optical transient absorption (TA), and THz TA spectroscopy. Optical spectroscopic results indicate that the high-temperature tetragonal phase still remains in the MAPbI3 thin films at low temperatures in addition to the major orthorhombic phase. The fast charge transfer from the orthorhombic phase to the tetragonal phase is likely to suppress the formation of excitons in the orthorhombic phase. Consequently, the near-band-edge optical responses of the photocarriers in both the tetragonal and orthorhombic phases of the MAPbI3 thin films are more accurately described by a free-carrier model, rather than an excitonic model even at low temperatures.

Prevalence of soluble peptidylarginine deiminase 4 (PAD4) and anti-PAD4 antibodies in autoimmune diseases.

The objectives of this study are to investigate the prevalence of PAD4 and anti-PAD4 antibodies (Abs) in autoimmune diseases and to clarify their association with anticitrullinated protein antibodies (ACPAs) and shared epitope (SE) in patients with rheumatoid arthritis (RA). Levels of human PAD4 and anti-PAD4 Abs in serum or plasma were measured using sandwich ELISA. Samples were obtained from patients with RA (n = 148), SLE (n = 36), or SS (n = 37) and from healthy controls (HCs; n = 40). Antibodies against cyclic citrullinated glucose-6-phosphate isomerase (GPI) (CCG)-2, CCG-7, anti-CEP-1, and anti-CCP Abs were also measured using ELISA. Patients with RA were genotyped for HLA-DRB1. The human PAD4 and anti-PAD4 Ab levels were compared with the ACPA and SE in patients with RA. The PAD4 levels were 111.9 U/ml in the RA, 30.4 U/ml in the SLE, 81.9 U/ml in the SS patients, and 46.6 U/ml in the HCs. The PAD4 levels were significantly higher in the RA than in the SLE patients or the HCs. Anti-PAD4 Abs were detected in 29.7 % of the patients with RA, but not in the patients with SLE or SS, nor in the HCs. In the RA patients, the PAD4 levels in the anti-PAD4 Ab-negative group were significantly higher than those in the anti-PAD4 Ab-positive group. Moreover, anti-CCG-2, CCG-7, CEP-1, and anti-CCP Ab levels were significantly higher in the anti-PAD4 Ab-positive group than in the anti-PAD4 Ab-negative group. In the RA patients, the PAD4 levels were not correlated with ACPAs. Neither PAD4 nor anti-PAD4 Abs were significantly correlated with the presence of SE alleles. The PAD4 levels were higher in RA than in SLE or HC. Anti-PAD4 Abs appeared specifically in patients with RA. Moreover, anti-PAD4 Abs were associated with ACPAs.

The coiled-coil domain of MURC/cavin-4 is involved in membrane trafficking of caveolin-3 in cardiomyocytes.

Muscle-restricted coiled-coil protein (MURC), also referred to as cavin-4, is a member of the cavin family that works cooperatively with caveolins in caveola formation and function. Cavins are cytoplasmic proteins with coiled-coil domains and form heteromeric complexes, which are recruited to caveolae in cells expressing caveolins. Among caveolins, caveolin-3 (Cav3) is exclusively expressed in muscle cells, similar to MURC/cavin-4. In the heart, Cav3 overexpression contributes to cardiac protection, and its deficiency leads to progressive cardiomyopathy. Mutations in the MURC/cavin-4 gene have been identified in patients with dilated cardiomyopathy. In the present study, we show the role of MURC/cavin-4 as a caveolar component in the heart. In H9c2 cells, MURC/cavin-4 was localized at the plasma membrane, whereas a MURC/cavin-4 mutant lacking the coiled-coil domain (ΔCC) was primarily localized to the cytoplasm. ΔCC bound to Cav3 and impaired membrane localization of Cav3 in cardiomyocytes. Additionally, although ΔCC did not alter Cav3 mRNA expression, ΔCC decreased the Cav3 protein level. MURC/cavin-4 and ΔCC similarly induced cardiomyocyte hypertrophy; however, ΔCC showed higher hypertrophy-related fetal gene expression than MURC/cavin-4. ΔCC induced ERK activation in cardiomyocytes. Transgenic mice expressing ΔCC in the heart (ΔCC-Tg mice) showed impaired cardiac function accompanied by cardiomyocyte hypertrophy and marked interstitial fibrosis. Hearts from ΔCC-Tg mice showed a reduction of the Cav3 protein level and activation of ERK. These results suggest that MURC/cavin-4 requires its coiled-coil domain to target the plasma membrane and to stabilize Cav3 at the plasma membrane of cardiomyocytes and that MURC/cavin-4 functions as a crucial caveolar component to regulate cardiac function.