Sulfur metabolism as a new therapeutic target of heart failure.

Sulfur-based redox signaling has long attracted attention as critical mechanisms underlying the development of cardiac diseases and resultant heart failure. Especially, post-translational modifications of cysteine (Cys) thiols in proteins mediate oxidative stress-dependent cardiac remodeling including myocardial hypertrophy, senescence, and interstitial fibrosis. However, we recently revealed the existence of Cys persulfides and Cys polysulfides in cells and tissues, which show higher redox activities than Cys and substantially contribute to redox signaling and energy metabolism. We have established simple evaluation methods that can detect polysulfides in proteins and inorganic polysulfides in cells and revealed that polysulfides abundantly expressed in normal hearts are dramatically catabolized by exposure to ischemic/hypoxic and environmental electrophilic stress, which causes vulnerability of the heart to mechanical load. Accumulation of hydrogen sulfide, a nucleophilic catabolite of persulfides/polysulfides, may lead to reductive stress in ischemic hearts, and perturbation of polysulfide catabolism can improve chronic heart failure after myocardial infarction in mice. This review focuses on the (patho)physiological role of sulfur metabolism in hearts, and proposes that sulfur catabolism during ischemic/hypoxic stress has great potential as a new therapeutic strategy for the treatment of ischemic heart failure.

Echinochrome Prevents Sulfide Catabolism-Associated Chronic Heart Failure after Myocardial Infarction in Mice.

Abnormal sulfide catabolism, especially the accumulation of hydrogen sulfide (H2S) during hypoxic or inflammatory stresses, is a major cause of redox imbalance-associated cardiac dysfunction. Polyhydroxynaphtoquinone echinochrome A (Ech-A), a natural pigment of marine origin found in the shells and needles of many species of sea urchins, is a potent antioxidant and inhibits acute myocardial ferroptosis after ischemia/reperfusion, but the chronic effect of Ech-A on heart failure is unknown. Reactive sulfur species (RSS), which include catenated sulfur atoms, have been revealed as true biomolecules with high redox reactivity required for intracellular energy metabolism and signal transduction. Here, we report that continuous intraperitoneal administration of Ech-A (2.0 mg/kg/day) prevents RSS catabolism-associated chronic heart failure after myocardial infarction (MI) in mice. Ech-A prevented left ventricular (LV) systolic dysfunction and structural remodeling after MI. Fluorescence imaging revealed that intracellular RSS level was reduced after MI, while H2S/HS- level was increased in LV myocardium, which was attenuated by Ech-A. This result indicates that Ech-A suppresses RSS catabolism to H2S/HS- in LV myocardium after MI. In addition, Ech-A reduced oxidative stress formation by MI. Ech-A suppressed RSS catabolism caused by hypoxia in neonatal rat cardiomyocytes and human iPS cell-derived cardiomyocytes. Ech-A also suppressed RSS catabolism caused by lipopolysaccharide stimulation in macrophages. Thus, Ech-A has the potential to improve chronic heart failure after MI, in part by preventing sulfide catabolism.

Myocardial TRPC6-mediated Zn2+ influx induces beneficial positive inotropy through ß-adrenoceptors.

Baroreflex control of cardiac contraction (positive inotropy) through sympathetic nerve activation is important for cardiocirculatory homeostasis. Transient receptor potential canonical subfamily (TRPC) channels are responsible for α1-adrenoceptor (α1AR)-stimulated cation entry and their upregulation is associated with pathological cardiac remodeling. Whether TRPC channels participate in physiological pump functions remains unclear. We demonstrate that TRPC6-specific Zn2+ influx potentiates ß-adrenoceptor (ßAR)-stimulated positive inotropy in rodent cardiomyocytes. Deletion of trpc6 impairs sympathetic nerve-activated positive inotropy but not chronotropy in mice. TRPC6-mediated Zn2+ influx boosts α1AR-stimulated ßAR/Gs-dependent signaling in rat cardiomyocytes by inhibiting ß-arrestin-mediated ßAR internalization. Replacing two TRPC6-specific amino acids in the pore region with TRPC3 residues diminishes the α1AR-stimulated Zn2+ influx and positive inotropic response. Pharmacological enhancement of TRPC6-mediated Zn2+ influx prevents chronic heart failure progression in mice. Our data demonstrate that TRPC6-mediated Zn2+ influx with α1AR stimulation enhances baroreflex-induced positive inotropy, which may be a new therapeutic strategy for chronic heart failure.

[Progress on tantalum rod implanting for the treatment of femur head necrosis].

Incorrect treatment for femur head necrosis can cause collapse of femoral head and tresult in severe harm for the patients (especially for the patient with middle-aged and young). The structure and mechanics characteristics of tantalum rod is similar to bone tissue, it higher strength and can adapt the internal environment of organism, so it has a large potency in treating femur head necrosis. Treatment of early femur head necrosis with tantalum rod implanting had alreadly widey applied at home and abroad, the method has the advantages of simple operation, little risk, less complication and beseems the patient with stage I - II of ARCO. But reasons that the difficult diagnosis of early femur head necrosis, localized effect of tantalum rod, different experience of medical worker,caused the contentions about effect of tantalum rod implanting. With development of science, tantalum rod implanting combined with correlative biotechnology should raise the effect in treating femur head necrosis.

[Experimental study on the isolated culture of osteocytes and identification of osteoblasts in rats].

OBJECTIVE: To establish a more stable method to isolate osteocytes in vitro, and then to find the differences with osteoblast biological characteristics. METHODS: Osteocytes and osteoblasts were isolated from the bone tissue of 3-day-old rats using sequential collagenase digestion. The cells were identified through cell morphology after 24 hours later. Alkaline phosphatase (ALP) kit was used to stain the first generation cells by Kaplow-way, the bone gla protein (BGP) of the cells were stained by immunocytochemitry. Measured ALP and computed its activity. RESULTS: Osteocytes and osteoblasts showed obviously differences in cell morphology. Osteocytes were star-shaped or dendrite-shaped within more dendrites, while osteoblasts were spindle-shaped with short dendrites. Osteocytes were negative for ALP, but osteoblasts were positive; Osteocytes were more positive for BGP, and osteoblasts were less positive. The secretion of ALP in osteocytes was lower than that of osteoblasts. CONCLUSION: Osteocytes can be isolated and cultured in vitro. These characteristics of osteocytes are apparently difference with those of osteoblasts.

[Relationship between the degree of displacement and the Baumnann angle in pediatric supracondylar humeral fractures].

OBJECTIVE: To analyze the relationship between the degree of displacement and Baumann angle in pediatric supracondylar humeral fractures by using Excel, and to guide treatment for humeral fractures of children. METHODS: From July 2010 to July 2011,56 children with humeral supracondylar fractures were collected (34 boys and 22 girls, 15 patients with radial deviation and 41 patients with ulnar deviation,ranging in age from 3 to 14 years). The data of the patients about fracture displacement and the Baumann angle measured by MB-Ruler were input in Excel and then were analyzed to obtain data fitting curve. RESULTS: There were close results between two methods, and the tangent of the radial deviation was more than tangent of ulnar deviation, which indicated that the influence of ulnar deviation was stronger than that of the radial deviation in pediatric supracondylar humeral fractures,so the correction should be paid attention to in clinic. When the radial deviation coefficient was less than -0.18 and ulnar deviation coefficient was more than 0.50,the Baumann angle would change to the reverse trend, so the angle range of Baumann in clinic should be between 65.70 and 96.77 degree. When the ulnar deviation factor was more than 0.15(including 0.15) and Baumann angle more than 82 degrees(including 82 degree), cubitus varus deformity occurred inevitably,so the practices and surgical reduction should be focused on in clinic. CONCLUSION: According to data curves analysis results,the influence of ulnar deviation is stronger than that of the radial deviation in pediatric supracondylar humeral fractures. When the ulnar deviation factor is more than 0.15 (including 0.15), correction should be focused on in order to prevent cubitus varus deformity.

[Influence of serum containing Liuwei Dihuang decoction (see text) on proliferation of osteoblasts under stretch-stress environment].

OBJECTIVE: To study influence of serum containing Liuwei Dihuang decoction (see text) on proliferation and differentiation of osteoblast form neonatal SD rats cultured in vitro at different times and different stretch stress. METHODS: After osteoblast cultured for 24 hours in the serum containing Liuwei Dihuang decoction (see text) and serum in control group, the 0.5 Hz frequency, 6% and 12% stretch-stress were added. The MTT1 and the activity of ALP were measured at the 12th and 24th hours, and the data were analyzed. RESULTS: 1. In the environment of stretch stress to the frequency of 0.5 Hz, and stretched for 24 hours, the osteoblast was stimulated under elongation rate of 6% and 12%; the proliferation and differentiation of osteoblast was more active under elongation rate of 12% than that of 6%. 2. There were no stimulating effects on osteoblast proliferation and differentiation of serum containing Liuwei Dihuiang decoction (see text) acted on osteoblast cells of SD rats cultured in vitro for a shot time. CONCLUSION: Stretch stress environment can enhance osteoblast proliferation and differentiation cultured in vitro.