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Satoshi Kurihara

Publications and source records attributed to Satoshi Kurihara.

At least 19 recordsLinked to original sources
PubMed2006

Intracellular mechanism of the negative inotropic effect induced by alpha1-adrenoceptor stimulation in mouse myocardium.

Alpha(1)-adrenoceptor stimulation (alpha(1)ARS) shows a positive inotropic effect in most mammalian myocardium. In mouse myocardium, however, alpha(1)ARS showed the negative inotropic effect, of which intracellular mechanisms are not fully clarified. The purpose of this study is to investigate the intracellular mechanism of the negative inotropic effect by alpha(1)ARS in C57BL/6 mouse myocardium. We used isolated ventricular papillary muscles of C57BL/6 strain mouse which is widely used for genetic manipulation. We simultaneously measured isometric tension and intracellular Ca(2+) concentration ([Ca(2+)](i)) using the aequorin method. In twitch contraction, phenylephrine concentration-dependently (1-100 microM) decreased tension without significant changes in the Ca(2+) transient, and these effects were completely blocked by prazosin (3 microM) or calphostin C (a PKC inhibitor, 1 microM). Phorbol 12-myristate 13-acetate (PMA) (a PKC activator, 1 microM) decreased tension as observed in phenylephrine. After PMA application, the negative inotropic effect of phenylephrine disappeared. To estimate the Ca(2+) sensitivity, tetanic contraction was produced, and the relation between [Ca(2+)](i) and tension at a steady state was measured. Phenylephrine (10 microM) decreased the Ca(2+) sensitivity, and PMA showed a similar Ca(2+) desensitizing effect. These results suggest that the negative inotropic effect of phenylephrine in mouse myocardium can be explained by the decrease in the Ca(2+) sensitivity through the activation of PKC. The present result indicates that the effect of alpha(1)ARS differs among species and strains of experiment animals. Thus, we should be careful about using the results of mouse myocardium to understand the functions of the human heart.

Animals↗
PubMed2006

Use of the Ca-shortening curve to estimate the myofilament responsiveness to Ca2+ in tetanized rat ventricular myocytes.

We previously estimated the myofilament responsiveness to Ca(2+) in isolated intact ventricular myocytes, using the steady-state relationship between cytosolic Ca(2+) concentration ([Ca(2+)](i)) and cell-shortening during tetanus (Ca-L trajectory). This method was useful and easy; however, it could not be used for a high dose of Ca sensitizer because the instantaneous plots after the application of Ca sensitizer did not make a fixed point of shortening (we used 5% shortening). Therefore we must produce another method to investigate Ca(2+) responsiveness. For an estimation of a wider range of the Ca-L trajectory, we fitted the Ca-L trajectory data with the Hill equation to construct the Ca-shortening curve. To fit this curve, we measured the maximal shortening, which was on average 31.6%. The value of [Ca(2+)](i) to produce the half-maximal shortening (Ca(50)) was dose-dependently decreased by EMD57033 (sensitization). Either isoproterenol or 3-isobutyl-1-methylxanthine increased Ca(50) (desensitization) with a concomitant increase in intracellular c-AMP. EMD57439, a selective PDE-III inhibitor, did not significantly increase the c-AMP concentration and produced little change in Ca(50). These results are in agreement with previous reports with skinned or intact multicellular preparations. The Ca-shortening curve constructed in intact cardiac myocytes can be used to estimate the myofibrillar responsiveness to Ca(2+) in a wide range of [Ca(2+)](i).

1-Methyl-3-isobutylxanthine↗
PubMed2006

Is the volume of the parathyroid gland a predictor of Maxacalcitol response in advanced secondary hyperparathyroidism?

We evaluated the relationship between the volume of parathyroid glands estimated by ultrasonography (US) and response of 22-oxa calcitriol (Maxacalcitol, OCT) in patients with secondary hyperparathyroidism (2HPT) to evaluate whether the volume can be a predictor of the OCT response. Eleven institutes participated in this study. Ninety-four patients with advanced 2HPT were enrolled. The volume of the parathyroid glands were estimated by US before and 6 months after OCT treatment. The response of OCT treatment was classified into three groups (Group A: i-PTH < 300 pg/mL; Group B: 300 pg/mL < or = i-PTH < 500 pg/mL; Group C: i-PTH > or = 500 pg/mL). Forty-eight patients were in Group A, 28 patients in Group B, and 18 patients in Group C. The PTH levels at the beginning and 6 months were 458.3-199.1 pg/mL (P < 0.0001) in Group A, 524.6-403.2 pg/mL (P = 0.007) in Group B and 736.7-613.6 pg/mL (ns) in Group C, respectively. The volume of the largest gland in Group B was significantly larger than that in Group A (96.2 vs. 343.2 mm3: P < 0.001). Clinical factors affecting response of OCT was evaluated by logistic regression analysis and only the volume of the largest gland was a significant factor. In the patients whose volume was less than 300 mm3, the OCT response was significantly effective. We conclude that the glandular volume of the largest parathyroid gland estimated by US can be a useful factor to predict the OCT response in patients with moderate or severe renal HPT.

Calcitriol↗
PubMed2006

Cross-bridge-dependent change in Ca2+ sensitivity is involved in the negative inotropic effect of nifedipine in aequorin-injected ferret ventricular muscles.

BACKGROUND: We hypothesized that the negative inotropic effect of nifedipine (Nif) on cardiac ventricular muscle is partly due to the cross-bridge-dependent decrease of Ca2+ sensitivity of the myofilaments as well as the decrease in Ca2+ influx. METHOD AND RESULTS: We used aequorin-injected ferret papillary muscles and measured the slope of the extra-Ca(2+)-tension relation which expresses the change in the Ca2+ sensitivity through the feedback from the cross-bridges. Twitch tension was decreased significantly by 0.5 micromol/L Nif accompanying a significant reduction of the Ca2+ transient peak. When Nif (0.2-0.5 micromol/L) was added to the solution with 8 mmol/L Ca2+, the slope of the extra-Ca2+-tension relation became steeper in a concentration-dependent manner, which was similar to the change in the slope when the concentration of Ca2+ was decreased from 8 to 1 mmol/L in the absence of Nif. BAY-K 8644 (0.3 micromol/L), a dihydropyridine receptor agonist, showed the opposite effect on the slope of the extra-Ca2+-tension relation to that observed in Nif. However, 2,3-butanedione monoxime (3 mmol/L), an inhibitor of the active cross-bridges, antagonized the effect of BAY-K 8644. CONCLUSION: Nif exerts its negative inotropic effect on cardiac muscle by suppressing Ca2+ binding to troponin C via the inhibition of the L-type Ca2+ channel, and by the cross-bridge-dependent decrease in the Ca2+ sensitivity, as in low extracellular Ca2+ concentration.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2006

Cross-bridge-dependent change of the Ca2+ sensitivity during relaxation in aequorin-injected tetanized ferret papillary muscles.

UNLABELLED: BACKGROUND The aim of the present study was to indicate the cross-bridge-dependent change in the Ca2+ affinity of troponin-C (TnC) during relaxation in an intact preparation, because the intracellular mechanism of relaxation is not fully understood, although several methods of evaluating global diastolic function have been reported. METHODS AND RESULTS: The aequorin method was used with intact ferret papillary muscles and a tetanic contraction was induced by a repetitive electrical stimulation in the presence of ryanodine. The extra-Ca2+, the transient increase in the intracellular Ca2+ concentration in response to a rapid reduction in muscle length, which reflects the change in the Ca2+ affinity of TnC because of cross-bridge detachment, was measured, and the cross-bridge-dependent change in the Ca2+ affinity of TnC was estimated by observing the change in the slope of the extra-Ca2+ -tension relation. The extra-Ca2+ -tension relation measured during relaxation became steeper than that during contraction in all cases. The extra-Ca2+ -tension relation became steeper in the presence of 20 mmol/L caffeine during contraction in all cases. CONCLUSION: During relaxation, the downstream-dependent change in the Ca2+ affinity of TnC was enhanced, compared with that during contraction, because of a decrease in the number of attached cross-bridges.

Aequorin↗
PubMed2005

Presenilin 2 regulates the systolic function of heart by modulating Ca2+ signaling.

Genetic studies of families with familial Alzheimer's disease have implicated presenilin 2 (PS2) in the pathogenesis of this disease. PS2 is ubiquitously expressed in various tissues including hearts. In this study, we examined cardiac phenotypes of PS2 knockout (PS2KO) mice to elucidate a role of PS2 in hearts. PS2KO mice developed normally with no evidence of cardiac hypertrophy and fibrosis. Invasive hemodynamic analysis revealed that cardiac contractility in PS2KO mice increased compared with that in their littermate controls. A study of isolated papillary muscle showed that peak amplitudes of Ca2+ transients and peak tension were significantly higher in PS2KO mice than those in their littermate controls. PS2KO mouse hearts exhibited no change in expression of calcium regulatory proteins. Since it has been demonstrated that PS2 in brain interacts with sorcin, which serves as a modulator of cardiac ryanodine receptor (RyR2), we tested whether PS2 also interacts with RyR2. Immmunoprecipitation analysis showed that PS2, sorcin, and RyR2 interact with each other in HEK-293 cells overexpressing these proteins or in mouse hearts. Immunohistochemistry of heart muscle indicated that PS2 colocalizes with RyR2 and sorcin at the Z-lines. Elevated Ca2+ attenuated the association of RyR2 with PS2, whereas the association of sorcin with PS2 was enhanced. The enhanced Ca2+ transients and contractility in PS2KO mice were observed at low extracellular [Ca2+] but not at high levels of [Ca2+]. Taken together, our results suggest that PS2 plays an important role in cardiac excitation-contraction coupling by interacting with RyR2.

Animals↗
PubMed2005

Auto-oscillations of skinned myocardium correlating with heartbeat.

Skinned myocardium (or myofibrils) exhibits auto-oscillations of sarcomere length and developed force called SPOC (SPontaneousOscillatoryContraction) under partial activation conditions. In SPOC, each sarcomere repeats the cycle of slow shortening and rapid lengthening, and the lengthening phase propagates sequentially to the adjacent sarcomeres in waves (SPOC wave). In this study, we analyzed the sarcomeric oscillation in SPOC in skinned myocardium of various animal species (rat, rabbit, dog, pig, and cow) with different heart rates. The period of oscillation, the sarcomere shortening velocity, and the velocity of SPOC wave, strongly correlated with the resting heart rate of the animal species. The shortening velocity in particular was proportional to the resting heart rate. We then examined the motile activity of each cardiac myosin by an in vitro motility assay. The sliding velocity of actin filaments, which is an index of the motile activity of myosin, also correlated with the resting heart rate but the relationship was not proportional. As a result, the ratio of sarcomere shortening velocity in SPOC to the sliding velocity of actin filaments was not constant but became higher with a higher heart rate. This suggests that the sarcomere shortening velocity in SPOC is modulated by some additional factors besides the motile activity of myosin, resulting in the proportional relationship between the shortening velocity of the sarcomere and the resting heart rate.

Actin Cytoskeleton↗
PubMed2005

alpha1-adrenoceptor stimulation potentiates L-type Ca2+ current through Ca2+/calmodulin-dependent PK II (CaMKII) activation in rat ventricular myocytes.

alpha1-Adrenoceptor stimulation (alpha1ARS) modulates cardiac muscle contraction under physiological conditions by means of changes in Ca2+ current through L-type channels (ICa,L) and Ca2+ sensitivity of the myofilaments. However, the cellular mechanisms of alpha1ARS are not fully clarified. In this study, we investigated the role of Ca2+/calmodulin-dependent PK II (CaMKII) in the regulation of ICa,L during alpha1ARS in isolated adult rat ventricular myocytes by using the perforated patch-clamp technique. CaMKII inhibition with 0.5 microM KN-93 abolished the potentiation in ICa,L observed during alpha1ARS by 10 microM phenylephrine. In the presence of PKC inhibitor (10 microM chelerythrine), the potentiation of ICa,L by phenylephrine also disappeared. In Western immunoblotting analysis, phenylephrine (> or =1 microM) increased the amount of autophosphorylated CaMKII (active CaMKII) significantly, and this increase was abolished by CaMKII inhibition or PKC inhibition. Also, we investigated changes in the subcellular localization of active CaMKII by using immunofluorescence microscopy and immunoelectron microscopy. Before alpha1ARS, active CaMKII was exclusively located just beneath the plasmalemma. However, after alpha1ARS, active CaMKII was localized close to transverse tubules, where most of L-type Ca2+ channels are located. From these results, we propose that CaMKII, which exists near transverse tubules, is activated and phosphorylated by alpha1ARS and that CaMKII activation directly potentiates ICa,L in rat ventricular myocytes.

Animals↗
PubMed2005

Mutations in human urate transporter 1 gene in presecretory reabsorption defect type of familial renal hypouricemia.

To date, 11 loss of function mutations in the human urate transporter 1 (hURAT1) gene have been identified in subjects with idiopathic renal hypouricemia. In the present studies we investigated the clinical features and the mutations in the hURAT1 gene in seven families with presecretory reabsorption defect-type renal hypouricemia and in one family with the postsecretory reabsorption defect type. Twelve affected subjects and 26 family members were investigated. Mutations were analyzed by PCR and the direct sequencing method. Urate-transporting activities of wild-type and mutant hURAT1 were determined by [14C]urate uptake in Xenopus oocytes. Mutational analysis revealed three previously reported mutations (G774A, A1145T, and 1639-1643 del-GTCCT) and a novel mutation (T1253G) in families with the presecretory reabsorption defect type. Neither mutations in the coding region of hURAT1 gene nor significant segregation patterns of the hURAT1 locus were detected in the postsecretory reabsorption defect type. All hURAT1 mutants had significantly reduced urate-transporting activities compared with wild type (P < 0.05; n = 12), suggesting that T1253G is a loss of function mutation, and hURAT1 is responsible for the presecretory reabsorption defect-type familial renal hypouricemia. Future studies are needed to identify a responsible gene for the postsecretory reabsorption defect-type familial renal hypouricemia.

Adolescent↗
PubMed2005

Evaluation of the cross-bridge-dependent change in the Ca2+ affinity of troponin C in aequorin-injected ferret ventricular muscles.

Ca2+ affinity of cardiac troponin C (TnC) is regulated by the active cross-bridges (downstream-dependent mechanism). In the present study, we showed one of the methods to evaluate the downstream-dependent change in the Ca2+ affinity of TnC during contraction using the aequorin-injected ferret papillary muscle. For this purpose, the tension-dependent change in the extra-Ca2+ (a transient increase in the intracellular Ca2+ concentration ([Ca2+]i) in response to a quick length reduction) was measured under various conditions. We examined whether the regression line between the magnitude of tension reduction and the magnitude of the normalized extra-Ca2+ (the extra-Ca2+ was divided by [Ca2+]i immediately before length change) (the normalized extra-Ca2+-tension relation) in twitch contraction can be used for the estimation of the downstream-dependent change in the Ca2+ affinity of TnC. The normalized extra-Ca2+-tension relation became shallow by EMD 57033 (EMD) (one of the Ca2+ sensitizers) and by an increase in Ca2+ concentration in the solution ([Ca2+]o) in a concentration-dependent manner. However, 2,3-butanedione monoxime (BDM) (one of the desensitizers) antagonized the effects of EMD and higher [Ca2+]o in a concentration-dependent manner. These effects of EMD and BDM were also observed in the normalized extra-Ca2+-tension relation in tetanic contraction. The normalized extra-Ca2+-tension relation became steep by shortening the initial muscle length before contraction in tetanic contraction. Length-tension relation in twitch contraction was significantly shifted upward by higher [Ca2+]o and EMD, but BDM showed the opposite effects on them in a concentration-dependent manner. Thus, the downstream-dependent change in the Ca2+ affinity of TnC which physiologically functions in intact cardiac muscle can be evaluated using the normalized extra-Ca2+-tension relation.

Aequorin↗
PubMed2005

Effect of MCI-196 (colestilan) as a phosphate binder on hyperphosphataemia in aemodialysis patients: a double-blind, placebo-controlled, short-term trial.

BACKGROUND: MCI-196 (colestilan), an anion exchange resin, is widely used as an anti-hypercholesterolaemic drug in Japan. To evaluate the efficacy and safety of MCI-196 as a phosphate binder, a double-blind, randomized, placebo-controlled prospective trial was conducted in Japanese end-stage renal disease patients with hyperphosphataemia on intermittent haemodialysis treatment. METHODS: Phosphate binders were discontinued during a 2-week washout period. Subsequently, patients whose serum phosphorus levels were > or =6.5 mg/dl, but <10 mg/dl were eligible to enter the treatment protocol. Patients were randomized to either MCI-196 6 g/day or placebo for 2 weeks. The efficacy and safety of MCI-196 were assessed in 33 and 46 patients, respectively. RESULTS: Serum phosphorus in the placebo group increased by 0.84+/-0.95 mg/dl (mean+/-SD), while serum phosphorus in the MCI-196 group decreased by 0.55+/-1.23 mg/dl. The difference between the two groups was statistically significant (P = 0.002). A reduction of > or =1 mg/dl in serum phosphorus was observed in 43% in the MCI-196 group and 0% of patients in the placebo group (P = 0.0122). Calcium-phosphorus (Ca x P) product, intact parathyroid hormone (iPTH) and low-density lipoprotein (LDL)-cholesterol in the MCI-196 group also decreased significantly compared with the placebo group, while serum calcium was unchanged. Adverse reactions were observed in 51.7% of the MCI-196 group and 29.4% of the placebo group (P = 0.2186). The most frequent adverse reactions in the MCI-196 group were gastrointestinal symptoms and signs, including constipation. CONCLUSIONS: The present findings suggest that the short-term administration of MCI-196 is effective in decreasing serum phosphorus in haemodialysis patients. Its long-term efficacy needs to be evaluated.

Bile Acids and Salts↗
PubMed2005

Parathyroid interventions for secondary hyperparathyroidism in hemodialyzed patients.

Although parathyroidectomy (PTX) is the ultimate treatment for secondary hyperparathyroidism (SHPT) that is resistant to medical treatment, recent advances in ultrasonographic techniques have increased the treatment options in Japan. Percutaneous ethanol injection therapy (PEIT) of the parathyroid was approved under the national health insurance system in 2004, and there have been trials of direct injection of vitamin D (VD) preparations. We followed 30 patients for at least 1 year who had undergone PEIT at the same institution. The overall mean concentration of intact parathyroid hormone (PTH) fell from 865.3+/-388.4 pg/mL to 291.9+/-277.8 pg/mL, or 34% of the pretreatment value. The effect was even more pronounced for one or two glands, with 68.4% reaching the target of intact PTH<or=300 pg/mL recommended in the K/DOQI guidelines, in comparison with 36.4% of cases of hypertrophy of three or four glands. The average time taken to achieve the target PTH concentration was 4 months. No correlation was found between the response to PEIT and the total parathyroid volume, or the volume of glands with suspected nodular hyperplasia. Cases in which PTH does not fall sufficiently after five or more injections should be considered refractory to PEIT and evaluated for PTX. Following PEIT, PTH falls relatively slowly, whereas after total PTX with forearm autograft the PTH concentration falls immediately and may still be less than 60 pg/mL 4 or 5 years later. Bone biopsies performed 1 year after total PTX with autograft showed a change from an osteitis fibrosa pattern to an adynamic bone disease pattern. In some cases of hypertrophy of three to four glands, markers of bone metabolism kept decreasing more than did PTH, corresponding to marked improvement in the patients' quality of life. Important considerations for treatment selection include: (i) ultrasonography of the cervical region as screening; (ii) earlier recognition of the limits of medical therapy; and (iii) the number of affected glands, the age of the patient, and the likely course postintervention.

Adult↗
PubMed2005

[Case of ANCA-associated glomerulonephritis detected at an early phase].

A 71-year-old man was admitted with low-grade fever, a high titer of CRP and ANCA. He was diagnosed as MPO-ANCA-associated vasculitis. On admission, his renal function was normal. Proteinuria and extra renal symptoms were not recognized. Only hematuria and hyaline cast were detected. A high titer of CRP and MPO-ANCA persisted. After obtaining informed consent, a renal biopsy was performed, revealing cellular crescentic glomerulonephritis and necrotizing vasculitis. The findings of the renal biopsy indicated an early phase of ANCA-associated nephritis. After MPSL pulse therapy, renal function was in the nomal range and proteinuria and hematuria disappeared. This present case demonstrated that early diagnosis and treatment are very important to sustain normal renal function if a high titer of MPO-ANCA is recognized in an elderly person without proteinuria.

Aged↗
PubMed2004

Cardiac-specific overexpression of sarcolipin inhibits sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA2a) activity and impairs cardiac function in mice.

Sarcolipin (SLN) inhibits the cardiac sarco(endo)plasmic reticulum Ca(2+) ATPase (SERCA2a) by direct binding and is superinhibitory if it binds through phospholamban (PLN). To determine whether overexpression of SLN in the heart might impair cardiac function, transgenic (TG) mice were generated with cardiac-specific overexpression of NF-SLN (SLN tagged at its N terminus with the FLAG epitope). The level of NF-SLN expression (the NF-SLN/PLN expression ratio) was equivalent to that which induces profound superinhibition when coexpressed with PLN and SERCA2a in HEK-293 cells. In TG hearts, the apparent affinity of SERCA2a for Ca(2+) was decreased compared with non-TG littermate control hearts. Invasive hemodynamic and echocardiographic analyses revealed impaired cardiac contractility and ventricular hypertrophy in TG mice. Basal PLN phosphorylation was reduced. In isolated papillary muscle subjected to isometric tension, peak amplitudes of Ca(2+) transients and peak tensions were reduced, whereas decay times of Ca(2+) transients and relaxation times of tension were increased in TG mice. Isoproterenol largely restored contractility in papillary muscle and stimulated PLN phosphorylation to wild-type levels in intact hearts. No compensatory changes in expression of SERCA2a, PLN, ryanodine receptor, and calsequestrin were observed in TG hearts. Coimmunoprecipitation indicated that overexpressed NF-SLN was bound to both SERCA2a and PLN, forming a ternary complex. These data suggest that NF-SLN overexpression inhibits SERCA2a through stabilization of SERCA2a-PLN interaction in the absence of PLN phosphorylation and through the inhibition of PLN phosphorylation. Inhibition of SERCA2a impairs contractility and calcium cycling, but responsiveness to beta-adrenergic agonists may prevent progression to heart failure.

Animals↗
PubMed2004

Comparative effects of bupivacaine and ropivacaine on intracellular calcium transients and tension in ferret ventricular muscle.

BACKGROUND: Recent evidence suggests that ropivacaine exerts markedly less cardiotoxicity compared with bupivacaine; however, the mechanisms are not fully understood at the molecular level. METHODS: Isolated ferret ventricular papillary muscles were microinjected with the Ca-binding photoprotein aequorin, and intracellular Ca transients and tension were simultaneously measured during twitch in the absence and presence of bupivacaine or ropivacaine. RESULTS: Bupivacaine and ropivacaine (10, 30, and 100 microm) reduced peak systolic [Ca]i and tension in a concentration-dependent manner. The effects were significantly greater for bupivacaine, particularly on tension (approximately twofold). The percentage reduction of tension was linearly correlated with that of [Ca]i for both anesthetics, with the slope of the relationship being approximately equal to 1.0 for ropivacaine and approximately equal to 1.3 for bupivacaine (slope difference, P < 0.05), suggesting that the cardiodepressant effect of ropivacaine results predominantly from inhibition of Ca transients, whereas bupivacaine suppresses Ca transients and the reaction beyond Ca transients, i.e., myofibrillar activation, as well. BAY K 8644, a Ca channel opener, abolished the inhibitory effects of ropivacaine on Ca transients and tension, whereas BAY K 8644 only partially inhibited the effects of bupivacaine, particularly the effects on tension. CONCLUSION: The cardiodepressant effect of bupivacaine is approximately twofold greater than that of ropivacaine. Bupivacaine suppresses Ca transients more markedly than does ropivacaine and reduces myofibrillar activation, which may at least in part underlie the greater inhibitory effect of bupivacaine on cardiac contractions. These results suggest that ropivacaine has a more favorable profile as a local anesthetic in the clinical settings.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2004

p38alpha mitogen-activated protein kinase plays a critical role in cardiomyocyte survival but not in cardiac hypertrophic growth in response to pressure overload.

The molecular mechanism for the transition from cardiac hypertrophy, an adaptive response to biomechanical stress, to heart failure is poorly understood. The mitogen-activated protein kinase p38alpha is a key component of stress response pathways in various types of cells. In this study, we attempted to explore the in vivo physiological functions of p38alpha in hearts. First, we generated mice with floxed p38alpha alleles and crossbred them with mice expressing the Cre recombinase under the control of the alpha-myosin heavy-chain promoter to obtain cardiac-specific p38alpha knockout mice. These cardiac-specific p38alpha knockout mice were born normally, developed to adulthood, were fertile, exhibited a normal life span, and displayed normal global cardiac structure and function. In response to pressure overload to the left ventricle, they developed significant levels of cardiac hypertrophy, as seen in controls, but also developed cardiac dysfunction and heart dilatation. This abnormal response to pressure overload was accompanied by massive cardiac fibrosis and the appearance of apoptotic cardiomyocytes. These results demonstrate that p38alpha plays a critical role in the cardiomyocyte survival pathway in response to pressure overload, while cardiac hypertrophic growth is unaffected despite its dramatic down-regulation.

Animals↗
PubMed2004

[The mechanism of contractile dysfunction in heart failure, focussing on SERCA2a function].

Cytosolic Ca(2+) is a key regulator of excitation-contraction coupling in myocardium. Myocardial contractile dysfunction in heart failure is characterized by a decrease in contraction and prolonged relaxation. These alterations are mainly due to changes in 1) intracellular Ca(2+) transients (CaT), 2) Ca(2+) sensitivity of the contractile elements, and/or 3) contractile proteins. It is useful to investigate the relationship between CaT and contraction for understanding of the mechanism of contractile dysfunction in heart failure. There are many reports regarding the alterations in CaT, Ca(2+) sensitivity, and contractile proteins in heart failure. Changes in the activity of the sarcoplasmic Ca(2+) pump protein, SERCA2a, may be involved in the altered contractility in heart failure. We generated cardiac-restricted overexpression of SERCA2a transgenic mice (TG) and non-transgenic littermates (NTG). To investigate the role of SERCA2a activity for ischemic heart, we used acidosis as a model of acute contractile dysfunction. During acidosis and recovery from acidosis, the peaks of CaT and tension in TG were significantly larger than those in NTG. These results suggest that an increase in the activity of SERCA2a could be beneficial to preserve contractility during acidosis and recovery. Thus, a disturbance of the intracellular Ca(2+) homeostasis is one of the key factors for the contractile dysfunction in heart failure.

Acidosis↗