Takuya Taniguchi

Sirolimus-Eluting Stent Versus Balloon Angioplasty for Sirolimus-Eluting Stent Restenosis: Insights From the j-Cypher Registry

Background— Optimal treatment strategies for restenosis of sirolimus-eluting stents (SES) have not been adequately addressed yet. Methods and Results— During the 3-year follow-up of 12 824 patients enrolled in the j-Cypher registry, 1456 lesions in 1298 patients underwent target-lesion revascularization (TLR). Excluding 362 lesions undergoing TLR for stent thrombosis or TLR using treatment modalities other than SES or balloon angioplasty (BA), 1094 lesions with SES-associated restenosis in 990 patients treated with either SES (537 lesions) or BA (557 lesions) constituted the study population for the analysis of recurrent TLR and stent thrombosis after the first TLR. Excluding 24 patients with both SES- and BA-treated lesions, 966 patients constituted the analysis set for the mortality outcome. Cumulative incidence of recurrent TLR in the SES-treated restenosis lesions was significantly lower than that in the BA-treated restenosis lesions (23.8% versus 37.7% at 2 years after the first TLR; P<0.0001). Among 33 baseline variables evaluated, only hemodialysis was identified to be the independent risk factor for recurrent TLR by a multivariable logistic regression analysis. After adjusting for confounders, repeated SES implantation was associated with a strong treatment effect in preventing recurrent TLR over BA (odds ratio, 0.44; 95% confidence interval, 0.32 to 0.61; P<0.0001). The 2-year mortality and stent thrombosis rates between the SES- and the BA-treated groups were 10.4% versus 10.8% (P=0.4) and 0.6% versus 0.6%, respectively. Conclusions— Repeated implantation of SES for SES-associated restenosis is more effective in preventing recurrent TLR than treatment with BA, without evidence of safety concerns.

MURC/Cavin-4 facilitates recruitment of ERK to caveolae and concentric cardiac hypertrophy induced by α1-adrenergic receptors

Significance Caveolae are recognized as a platform for preassembled complexes of receptors, signal components, and their targets, facilitating efficient and specific cellular responses at the plasma membrane. ERK is activated at the plasma membrane and an important molecule that has been well studied for its integral role in signal transduction events during physiological adaptation and pathological manifestation. Here we show that although muscle-restricted coiled-coil protein (MURC)/Cavin-4, a muscle-specific caveola component, is dispensable for caveolar formation in cardiomyocytes, MURC/Cavin-4 serves as an ERK-recruiting protein in the caveolae within cardiomyocytes. The recruiting function of MURC/Cavin-4 is necessary to elicit efficient signaling of the α1-adrenergic receptor–ERK cascade in concentric cardiac hypertrophy. Our findings provide unique insight into the molecular mechanisms underlying caveola-mediated signaling in cardiac hypertrophy. The actions of catecholamines on adrenergic receptors (ARs) induce sympathetic responses, and sustained activation of the sympathetic nervous system results in disrupted circulatory homeostasis. In cardiomyocytes, α1-ARs localize to flask-shaped membrane microdomains known as “caveolae.” Caveolae require both caveolin and cavin proteins for their biogenesis and function. However, the functional roles and molecular interactions of caveolar components in cardiomyocytes are poorly understood. Here, we showed that muscle-restricted coiled-coil protein (MURC)/Cavin-4 regulated α1-AR–induced cardiomyocyte hypertrophy through enhancement of ERK1/2 activation in caveolae. MURC/Cavin-4 was expressed in the caveolae and T tubules of cardiomyocytes. MURC/Cavin-4 overexpression distended the caveolae, whereas MURC/Cavin-4 was not essential for their formation. MURC/Cavin-4 deficiency attenuated cardiac hypertrophy induced by α1-AR stimulation in the presence of caveolae. Interestingly, MURC/Cavin-4 bound to α1A- and α1B-ARs as well as ERK1/2 in caveolae, and spatiotemporally modulated MEK/ERK signaling in response to α1-AR stimulation. Thus, MURC/Cavin-4 facilitates ERK1/2 recruitment to caveolae and efficient α1-AR signaling mediated by caveolae in cardiomyocytes, which provides a unique insight into the molecular mechanisms underlying caveola-mediated signaling in cardiac hypertrophy.

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.

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.

Arterial stiffness, endothelial dysfunction and recurrent angina post-chemotherapy

### Learning Point for Clinicians This case highlights the mechanisms of predicted angina pectoris several days after multi-drug chemotherapeutic regimen for relapsed multiple myeloma. Physicians should recognize that cumulative chemotherapy could exacerbate both arterial stiffness and endothelial dysfunction and result in transiently frequent coronary vasospasm even with clinically permissible doses of vincristine–adriamycin–dexamethasone chemotherapy or thalidomide. In April 2006, a 61-year-old male without coronary risks was referred to our cardiology department because of severe chest oppression 7 days after vincristine–adriamycin–dexamethasone chemotherapy (VAD) for relapsed multiple myeloma. In July 2003, he was diagnosed with multiple myeloma IgA lambda (Durie-Salmon stage IIIA), and received three monthly cycles of VAD, stem cell mobilization with cyclophosphamide and melphalan-based autologous peripheral blood stem cell transplantation. In June 2005, he started thalidomide 200–300 mg daily for a relapse of myeloma. Afterwards, he experienced resting chest discomfort lasting several minutes in July 2005, and severe chest squeezing and …

Rapid Progression of Left Ventricular Hypertrophy

Patients with hypertrophic cardiomyopathy sometimes develop extreme hypertrophy in the left ventricle. A 78-year-old woman showed rapid progression of left ventricular hypertrophy. She was referred to our hospital at the age of 73 years because of left ventricular hypertrophy on seen on ECG. …