Takashi Sato

Sorcin interacts with sarcoplasmic reticulum Ca2+–ATPase and modulates excitation–contraction coupling in the heart

Abstract Sorcin is a 21.6–kDa Ca2+ binding protein of the penta–EF handnfamily. Several studies have shown that sorcin modulates multiple proteinsninvolved in excitation–contraction (E–C) coupling in the heart, such as thencardiac ryanodine receptor (RyR2), L–type Ca2+ channel, and Na+–Ca2+nexchanger, while it has also been shown to be phosphorylated by cAMP–dependentnprotein kinase (PKA). To elucidate the effects of sorcin and itsnPKA–dependent regulation on E–C coupling in the heart, we identified thenPKA–phosphorylation site of sorcin, and found that serine178 was preferentiallynphosphorylated by PKA and dephosphorylated by protein phosphatase–n1. Isoproterenol allowed sorcin to translocate to the sarcoplasmic reticulumn(SR). In addition, adenovirus–mediated overexpression of sorcin in adult ratncardiomyocytes significantly increased both the rate of decay of the Ca2+ntransient and the SR Ca2+ load. An assay of oxalate–facilitated Ca2+ uptakenshowed that recombinant sorcin increased Ca2+ uptake in a dose–dependentnmanner. These data suggest that sorcin activates the Ca2+–uptake function innthe SR. In UM–X7. 1 cardiomyopathic hamster hearts, the relative amount ofnsorcin was significantly increased in the SR fraction, whereas it was significantly decreased in whole–heart homogenates. In failing hearts, PKA–phosphorylatednsorcin was markedly increased, as assessed using a back–phosphorylationnassay with immunoprecipitated sorcin. Our results suggest thatnsorcin activates Ca2+–ATPase–mediated Ca2+ uptake and restores SR Ca2+ncontent, and may play critical roles in compensatory mechanisms in bothnCa2+ homeostasis and cardiac dysfunction in failing hearts.

A Case of Vertebral Artery Dissection Associated with Morning Blood Pressure Surge

We report a case of a middle-aged man who suffered a cerebral infarction resulting from dissection of a vertebral artery associated with morning blood pressure surge. A 56-year-old man was transferred to our hospital with dizziness and vomiting in the early morning on a cold day in winter. He reported that he had been standing in front of the sink after bathing when he suddenly felt dizzy and fell down. He did not lose consciousness, and by the time he reached the hospital by ambulance, his dizziness had subsided, but he complained of severe headache and vomited 3 times. On admission, he was alert, and there were no neurological or radiological abnormalities (CT, MR angiography) in the brain. However, infarction in the left cerebellar hemisphere was detected by brain MRI on the 5th day of hospitalization. String sign of the left vertebral artery was noted by angiography, confirming the diagnosis of dissection of the left vertebral artery. Ambulatory blood pressure monitoring was performed after discharge. Although the mean 24-h blood pressure was in the normal range, a marked morning blood pressure rise was observed. We speculated that the acute rise of blood pressure in the early morning might have contributed to the dissection of the vertebral artery.

Norepinephrine spillover during exercise as a novel parameter to evaluate the severity of heart failure

BackgroundThe washout rate (WR) of 123I-metaiodobenzylguanidine (MIBG) is now widely used for assessing the severity of heart failure. Although the WR of MIBG is usually measured at rest, the assessment of WR of MIBG during exercise might have a different clinical relevance. In this study, we measured the WR rate of MIBG during low-grade exercise and studied the clinical importance of this novel index.MethodsTwenty-four patients with dilated cardiomyopathy (DCM) were enrolled in this study. Planar images were obtained 20xa0minutes after MIBG injection (first image) and after 270xa0minutes (second image); the third image was obtained after 15xa0minutes of low-grade (10xa0W) bicycle ergometer exercise (300xa0minutes after MIBG injection). The decay of the specific counts was calculated from the first two images. The estimated third counts were calculated from the resting decay and were compared with the actual third counts.ResultsIn the receiver operating characteristic (ROC) curve analysis, we set a 10% decrease from the estimated counts as a cut-off value for severe heart failure (New York Heart Association [NYHA] Class IIm or worse). In 15 patients, the actual third count value was within 10% of the estimated count (N-group). In nine patients, the WR during exercise was high, and the actual third count values showed more than a 10% decrease from the estimated count value (H-group). In the H-group, 78% of the patients were in NYHA class IIm or III. In contrast, in the N-group, no patient had NYHA class III, and only 20% of the patients were in class IIm. The brain natriuretic peptide (BNP) level was significantly higher in the H-group than in the N-group (525xa0±xa0263xa0pg/mL vs 176xa0±xa0144xa0pg/mL; Pxa0<xa0.01). No significant differences were observed in heart/mediastinal (H/M) activity ratio, the regular WR, and left ventricular ejection fraction values between the two groups.ConclusionsThe WR of MIBG during exercise may be an independent prediction variable, with a clinical relevance different from that of the WR at rest. This measurement could be used as a new index for assessing the severity of heart failure.

High ambient pressure produces hypertrophy and up-regulates cardiac sarcoplasmic reticulum Ca2+ regulatory proteins in cultured rat cardiomyocytes.

Previously, we demonstrated in vivo that the nature of the alterations in sarcoplasmic reticulum (SR) function and SR Ca2+ regulatory proteins depends both on the type of mechanical overload imposed and on the duration of the heart disorder. The purpose of the present study was to determine in vitro whether an extrinsic mechanical overload (in the form of high ambient pressure) would cause an up-regulation of ryanodine receptor (RyR) and Ca2+-ATPase, as we previously reported mildly pressure-overloaded, hypertrophied rat hearts. Primary cultures of neonatal rat cardiomyocytes were prepared and high ambient pressure was produced using an incubator and pressure-overloading apparatus. Cells were exposed to one of two conditions for 72 h: atmospheric pressure conditions (APC) or high pressure conditions (HPC; HPC=APC+200 mmHg). The expression levels of RyR and Ca2+-ATPase were quantified and functional characteristics were monitored. The cell area was significantly greater under HPC. After 6 h exposure, the physiological properties of cardiomyocytes were impaired, but they returned to the baseline level within 24 h. After 24 h exposure, the expression level of RyR was significantly higher under HPC, and for Ca2+-ATPase, the expression level was significantly higher under HPC after 6 h exposure. HPC caused hypertrophy and up-regulated the expression of Ca2+ regulatory proteins and their genes. We suggest that this in vitro pressure-overloading model may prove useful, as is a stretch-overloading model, for investigation of the intracellular Ca2+ regulatory pathways responsible for the development of cardiac hypertrophy.