Angiotensin-converting enzyme 2 (ACE2) plays a critical role against myocardial infarction (MI). We hypothesized that activation of intrinsic ACE2 would be protective against ischemia-induced cardiac pathophysiology. Diminazine aceturate (DIZE), a small molecule ACE2 activator has been used to evaluate this hypothesis. DIZE (15 mg/kg/day, s.c.) was injected two days prior to MI surgery and continued throughout the study-period. MI rats showed a 62% decrease in fractional shortening (FS,%) [control (Con): 51.1 ± 3.2; DIZE alone (D) : 52.1 ± 3.2; MI (M): 19.1± 3.0], a 55% decrease in contractility (dP/dtmax mmHg/s) (Con: 9480 ± 425.3; D: 9585 ± 597.4; M: 4251 ± 657.7), and a 27% increase in ventricular hypertrophy [VH, mg/mm (Con: 26.5 ± 1.5; D: 26.9 ± 1.4; M: 33.4± 1.1)]. DIZE attenuated the MI-induced decrease in FS by 89%, improved dP/dtmax by 92%, and reversed VH by 18%. MI also significantly increased ACE and angiotensin type 1 receptor levels while decreased ACE2 activity by 40% (Con: 246.2 ± 25.1; D: 254.2 ± 20.6; M: 148.9 ± 29.2, RFU/min), which was reversed by DIZE treatment. Thus, DIZE treatment decreased the infarct area, attenuated LV remodeling post-MI and restored normal balance of the cardiac renin angiotensin system. Additionally, DIZE treatment increased circulating endothelial progenitor cells, increased engraftment of cardiac progenitor cells and decreased inflammatory cells in peri-infarct cardiac regions. All of the beneficial effects associated with DIZE treatment were abolished by C-16, an ACE2 inhibitor. Collectively, DIZE and DIZE-like small molecules may represent promising new therapeutic agents for MI.

BackgroundLower leg ischemia, myopathy, and limb dysfunction are distinguishing features of peripheral artery disease (PAD). The myopathy of PAD is characterized by myofiber degeneration in association with extracellular matrix expansion, and increased expression of transforming growth factor-beta 1 (TGF-β1; a pro-fibrotic cytokine). In this study, we evaluated cellular expression of TGF-β1 in gastrocnemius of control (CTRL) and PAD patients and its relationship to deposited collagen, fibroblast accumulation and limb hemodynamics.MethodsGastrocnemius biopsies were collected from PAD patients with claudication (PAD-II; N = 25) and tissue loss (PAD-IV; N = 20) and from CTRL patients (N = 20). TGF-β1 in slide-mounted specimens was labeled with fluorescent antibodies and analyzed by quantitative wide-field, fluorescence microscopy. We evaluated co-localization of TGF-β1 with vascular smooth muscle cells (SMC) (high molecular weight caldesmon), fibroblasts (TE-7 antigen), macrophages (CD163), T cells (CD3) and endothelial cells (CD31). Collagen was stained with Masson Trichrome and collagen density was determined by quantitative bright-field microscopy with multi-spectral imaging.ResultsCollagen density increased from CTRL to PAD-II to PAD-IV specimens (all differences p < 0.05) and was prominent around microvessels. TGF-β1 expression increased with advancing disease (all differences p < 0.05), correlated with collagen density across all specimens (r = 0.864; p < 0.001), associated with fibroblast accumulation, and was observed exclusively in SMC. TGF-β1 expression inversely correlated with ankle-brachial index across PAD patients (r = −0.698; p < 0.001).ConclusionsOur findings support a progressive fibrosis in the gastrocnemius of PAD patients that is caused by elevated TGF-β1 production in the SMC of microvessels in response to tissue hypoxia.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0790-3) contains supplementary material, which is available to authorized users.

Evidence indicates that cerebral blood flow is both increased and diminished in astronauts on return to Earth. Data from ground-based animal models simulating the effects of microgravity have shown that decrements in cerebral perfusion are associated with enhanced vasoconstriction and structural remodeling of cerebral arteries. Based on these results, the purpose of this study was to test the hypothesis that 13 d of spaceflight [Space Transportation System (STS)-135 shuttle mission] enhances myogenic vasoconstriction, increases medial wall thickness, and elicits no change in the mechanical properties of mouse cerebral arteries. Basilar and posterior communicating arteries (PCAs) were isolated from 9-wk-old female C57BL/6 mice for in vitro vascular and mechanical testing. Contrary to that hypothesized, myogenic vasoconstrictor responses were lower and vascular distensibility greater in arteries from spaceflight group (SF) mice (n=7) relative to ground-based control group (GC) mice (n=12). Basilar artery maximal diameter was greater in SF mice (SF: 236±9 μm and GC: 215±5 μm) with no difference in medial wall thickness (SF: 12.4±1.6 μm; GC: 12.2±1.2 μm). Stiffness of the PCA, as characterized via nanoindentation, was lower in SF mice (SF: 3.4±0.3 N/m; GC: 5.4±0.8 N/m). Collectively, spaceflight-induced reductions in myogenic vasoconstriction and stiffness and increases in maximal diameter of cerebral arteries signify that elevations in brain blood flow may occur during spaceflight. Such changes in cerebral vascular control of perfusion could contribute to increases in intracranial pressure and an associated impairment of visual acuity in astronauts during spaceflight.

Hypotonic saline solutions have been used for over five decades to treat children with diarrheal dehydration. However, concern has recently been raised about the potential for iatrogenic hyponatremia as a result of this therapy. We reviewed the medical records of 531 otherwise healthy children with gastroenteritis who had been admitted to the hospital for intravenous fluid therapy. We retrospectively collected data on 141 of these children who had received two serum electrolytes (one upon admission and the other 4-24 h thereafter). The remaining 390 children were excluded because their charts lacked the required data. We analyzed data in 124 of these 141 patients whose initial serum sodium (Na) level was between 130-150 mEq/l and excluded 17 patients whose admission serum sodium fell outside this range. All patients were treated with intravenous hypotonic fluids (5% dextrose in 0.2% saline, n = 4; 5% dextrose in 0.3% saline, n = 102; 5% dextrose in 0.45% saline, n = 18 patients) as maintenance fluid therapy or maintenance fluid plus deficit therapy; 100 of these children had received an initial saline bolus of 21.05 +/- 8.5 ml/kg upon admission. The serum Na level decreased by 1.7 +/- 4.3 mEq/l in the whole group. Of the 97 children with isonatremia (Na 139.5 +/- 2.7 mEq/l) on admission, 18 (18.5%) developed mild hyponatremia (Na 133.4 +/- 0.9 mEq/l, range 131-134), with a decrease in serum Na of 5.7 +/- 3.1 mEq/l, and 79 remained isonatremic (Na 138.3 +/- 2.7 mEq/l), with a decrease in serum Na of 1.8 +/- 3.4 mEq/l (p < 0.0005). There was no significant difference in type, rate, or amount of intravenous fluid or saline bolus (26.1 +/- 10.4 vs. 20.2 +/- 8.6 ml/kg, respectively) administered in these two groups. Children who became hyponatremic were older (5.8 +/- 2.7 years) than those who remained isonatremic (2.8 +/- 3.1 years) (p < 0.0005), but there was no statistical difference in gender, degree of dehydration, and severity of metabolic acidosis between the two groups. Although serum Na increased by 3.9 +/- 2.5 mEq/l in 19 patients with mild hyponatremia upon admission (Na 132.8 +/- 1.3 to 136.7 +/- 2.6 mEq/l) and 73% of these became isonatremic, hypotonic saline solutions have the potential to cause hyponatremia in children with gastroenteritis and isonatremic dehydration.