Hiromichi Ueda

Bcl-2-like protein 13 is a mammalian Atg32 homologue that mediates mitophagy and mitochondrial fragmentation.

Damaged mitochondria are removed by mitophagy. Although Atg32 is essential for mitophagy in yeast, no Atg32 homologue has been identified in mammalian cells. Here, we show that Bcl-2-like protein 13 (Bcl2-L-13) induces mitochondrial fragmentation and mitophagy in mammalian cells. First, we hypothesized that unidentified mammalian mitophagy receptors would share molecular features of Atg32. By screening the public protein database for Atg32 homologues, we identify Bcl2-L-13. Bcl2-L-13 binds to LC3 through the WXXI motif and induces mitochondrial fragmentation and mitophagy in HEK293 cells. In Bcl2-L-13, the BH domains are important for the fragmentation, while the WXXI motif facilitates mitophagy. Bcl2-L-13 induces mitochondrial fragmentation in the absence of Drp1, while it induces mitophagy in Parkin-deficient cells. Knockdown of Bcl2-L-13 attenuates mitochondrial damage-induced fragmentation and mitophagy. Bcl2-L-13 induces mitophagy in Atg32-deficient yeast cells. Induction and/or phosphorylation of Bcl2-L-13 may regulate its activity. Our findings offer insights into mitochondrial quality control in mammalian cells.

Prevention of Contrast-Induced Nephropathy by Bolus Injection of Sodium Bicarbonate in Patients With Chronic Kidney Disease Undergoing Emergent Coronary Procedures

We conducted a prospective study to determine whether a bolus injection of sodium bicarbonate before emergent coronary procedures in patients with chronic kidney disease (CKD) might prevent contrast-induced nephropathy (CIN). We enrolled 59 patients with CKD, defined by a serum creatinine concentration of >1.1 mg/dl or an estimated glomerular filtration rate of <60 ml/min, who were scheduled at admission to undergo an emergent coronary procedure. The patients were randomized to receive a bolus intravenous injection of 154 mEq/L of sodium bicarbonate (n = 30) or sodium chloride (n = 29) at the dose of 0.5 ml/kg, before contrast administration, followed by infusion of 154 mEq/L sodium bicarbonate at 1 ml/kg/hour for 6 hours in both groups. The primary end point was the occurrence of CIN, defined as an increase by > 25% or > 0.5 mg/dl of the serum creatinine level within 2 days after the procedure. In the sodium bicarbonate group, the serum creatinine concentration remained unchanged within 2 days of contrast administration (from 1.32 ± 0.46 to 1.38 ± 0.60 mg/dl, p = 0.33). In contrast, it had increased in the sodium chloride group (1.51 ± 0.59 to 1.91 ± 1.19 mg/dl, p = 0.006). The incidence of CIN was significantly lower in the sodium bicarbonate group than in the sodium chloride group (3.3% vs 27.6%, p = 0.01). In conclusion, rapid alkalization by bolus injection of sodium bicarbonate was effective for the prevention of CIN in patients with CKD undergoing emergent procedures.

Autophagy-mediated degradation is necessary for regression of cardiac hypertrophy during ventricular unloading

Cardiac hypertrophy occurs in response to a variety of stresses as a compensatory mechanism to maintain cardiac output and normalize wall stress. Prevention or regression of cardiac hypertrophy can be a major therapeutic target. Although regression of cardiac hypertrophy occurs after control of etiological factors, the molecular mechanisms remain to be clarified. In the present study, we investigated the role of autophagy in regression of cardiac hypertrophy. Wild-type mice showed cardiac hypertrophy after continuous infusion of angiotensin II for 14 days using osmotic minipumps, and regression of cardiac hypertrophy was observed 7 days after removal of the minipumps. Autophagy was induced during regression of cardiac hypertrophy, as evidenced by an increase in microtubule-associated protein 1 light chain 3 (LC3)-II protein level. Then, we subjected cardiac-specific Atg5-deficient (CKO) and control mice (CTL) to angiotensin II infusion for 14 days. CKO and CTL developed cardiac hypertrophy to a similar degree without contractile dysfunction. Seven days after removal of the minipumps, CKO showed significantly less regression of cardiac hypertrophy compared with CTL. Regression of pressure overload-induced cardiac hypertrophy after unloading was also attenuated in CKO. These results suggest that autophagy is necessary for regression of cardiac hypertrophy during unloading of neurohumoral and hemodynamic stress.

Usefulness of Cardiac Iodine-123 Meta-Iodobenzylguanidine Imaging to Improve Prognostic Power of Seattle Heart Failure Model in Patients With Chronic Heart Failure

The Seattle Heart Failure Model (SHFM) is a validated prediction model that estimates the mortality in patients with chronic heart failure (CHF) using commonly obtained information, including clinical data, laboratory test results, medication use, and device implantation. In addition, cardiac iodine-123 meta-iodobenzylguanidine (MIBG) imaging provides prognostic information for patients with CHF. However, the long-term predictive value of combining the SHFM and cardiac MIBG imaging in patients with CHF has not been elucidated. To prospectively investigate whether cardiac iodine-123 MIBG imaging provides additional prognostic value to the SHFM in patients with CHF, we studied 106 outpatients with CHF who had radionuclide left ventricular ejection fraction < 40% (30 ± 8%). The SHFM score was obtained at enrollment, and the cardiac MIBG washout rate (WR) was calculated from anterior chest images obtained at 20 and 200 minutes after isotope injection. During a mean follow-up of 6.8 ± 3.5 years (range 0 to 13), 32 of 106 patients died from cardiac causes. A multivariate Cox analysis revealed that the WR (p = 0.0002) and SHFM score (p = 0.0091) were independent predictors of cardiac death. Kaplan-Meier analysis showed that patients with an abnormal WR (> 27%) had a significantly greater risk of cardiac death than did those with a normal WR for both those with a SHFM score of ≥ 1 (relative risk 3.3, 95% confidence interval 1.2 to 9.7, p = 0.01) and a SHFM score of ≤ 0 (relative risk 3.4, 95% confidence interval 1.2 to 9.6, p = 0.004). In conclusion, the cardiac MIBG WR provided additional prognostic information to the SHFM score for patients with CHF.

Increased intraatrial conduction abnormality assessed by P-wave signal-averaged electrocardiogram in patients with Brugada syndrome.

Background:  Atrial fibrillation (AF) is observed in patients with Brugada syndrome (BS), especially those showing coved‐type electrocardiogram (ECG) pattern. Using P‐wave signal‐averaged ECG (P‐SAE), we investigated whether increased intraatrial conduction abnormality contributed to AF generation in BS patients.