No abstract

BackgroundCoronary artery disease leading to myocardial ischemia is the most common cause of heart failure. Apelin (APLN), the endogenous peptide ligand of the APJ receptor, has emerged as a novel regulator of the cardiovascular system.Methods and ResultsHere we show a critical role of APLN in myocardial infarction (MI) and ischemia‐reperfusion (IR) injury in patients and animal models. Myocardial APLN levels were reduced in patients with ischemic heart failure. Loss of APLN increased MI‐related mortality, infarct size, and inflammation with drastic reductions in prosurvival pathways resulting in greater systolic dysfunction and heart failure. APLN deficiency decreased vascular sprouting, impaired sprouting of human endothelial progenitor cells, and compromised in vivo myocardial angiogenesis. Lack of APLN enhanced susceptibility to ischemic injury and compromised functional recovery following ex vivo and in vivo IR injury. We designed and synthesized two novel APLN analogues resistant to angiotensin converting enzyme 2 cleavage and identified one analogue, which mimicked the function of APLN, to be markedly protective against ex vivo and in vivo myocardial IR injury linked to greater activation of survival pathways and promotion of angiogenesis.ConclusionsAPLN is a critical regulator of the myocardial response to infarction and ischemia and pharmacologically targeting this pathway is feasible and represents a new class of potential therapeutic agents.

Rationale Diabetic cardiovascular complications are reaching epidemic proportions. Angiotensin-converting enzyme-2 (ACE2) is a negative regulator of the renin-angiotensin system. We hypothesize that loss of ACE2 exacerbates cardiovascular complications induced by diabetes. Objective To define the role of ACE2 in diabetic cardiovascular complications. Methods and Results We used the well-validated Akita mice, a model of human diabetes, and generated double-mutant mice using the ACE2 knockout (KO) mice (Akita/ACE2−/y). Diabetic state was associated with increased ACE2 in Akita mice, whereas additional loss of ACE2 in these mice leads to increased plasma and tissue angiotensin II levels, resulting in systolic dysfunction on a background of impaired diastolic function. Downregulation of SERCA2 and lipotoxicity were equivalent in Akita and Akita/ACE2KO hearts and are likely mediators of the diastolic dysfunction. However, greater activation of protein kinase C and loss of Akt and endothelial nitric oxide synthase phosphorylation occurred in the Akita/ACE2KO hearts. Systolic dysfunction in Akita/ACE2KO mice was linked to enhanced activation of NADPH oxidase and metalloproteinases, resulting in greater oxidative stress and degradation of the extracellular matrix. Impaired flow-mediated dilation in vivo correlated with increased vascular oxidative stress in Akita/ACE2KO mice. Treatment with the AT1 receptor blocker, irbesartan rescued the systolic dysfunction, normalized altered signaling pathways, flow-mediated dilation, and the increased oxidative stress in the cardiovascular system. Conclusions Loss of ACE2 disrupts the balance of the renin-angiotensin system in a diabetic state and leads to an angiotensin II/AT1 receptor-dependent systolic dysfunction and impaired vascular function. Our study demonstrates that ACE2 serves as a protective mechanism against diabetes-induced cardiovascular complications.

An approach preventing contact to ambient air during transfer from liquid environment for electrochemical treatment to UHV environment for surface analysis by X-Ray Photoelectron Spectroscopy and Time-of-Flight Secondary Ion Mass Spectrometry was applied to study the mechanisms of Cr and Mo enrichments in the passive oxide film formed on 316L austenitic stainless steel. Starting from the air-formed native oxide-covered surface, exposures were conducted in aqueous sulfuric acid solution first at open circuit potential and then under anodic polarization in the passive range. At open circuit potential the thickness of the bi-layered oxide film was observed to decrease and the enrichments of both Cr(III) and Mo, mostly Mo(VI), to markedly increase as well as the film hydroxylation. This is due to preferential dissolution of the Fe(III) oxide/hydroxide, not compensated by oxide growth in the absence of an electric field established by anodic polarization. Anodic polarization in the passive domain causes the bi-layered structure of the oxide film to re-grow by oxidation of iron, chromium and molybdenum, without impacting the Cr enrichment and only slightly mitigating the Mo enrichment. De-hydroxylation of the inner layer is also promoted upon anodic polarization. These results show that the treatment of the surface oxide film in acid solution at open circuit potential enhances Cr and Mo enrichments and promotes hydroxylation. Passivation by anodic polarization allows dehydroxylation, yielding more Cr oxide, without markedly affecting the Mo enrichment, also beneficial for the corrosion resistance.

Abstract-Loss of angiotensin (Ang)-converting enzyme 2 (ACE2) and inability to metabolize Ang II to Ang 1-7 perpetuate the actions of Ang II after biomechanical stress and exacerbate early adverse myocardial remodeling. Ang receptor blockers are known to antagonize the effect of Ang II by blocking Ang II type 1 receptor (AT 1 R) and also by upregulating the ACE2 expression. We directly compare the benefits of AT 1 R blockade versus enhancing Ang 1-7 action in pressure-overload-induced heart failure in ACE2 knockout mice. AT 1 R blockade and Ang 1-7 both resulted in marked recovery of systolic dysfunction in pressure-overloaded ACE2-null mice. Similarly, both therapies attenuated the increase in NADPH oxidase activation by downregulating the expression of Nox2 and p47 phox subunits and also by limiting the p47 phox phosphorylation. Biomechanical stress-induced increase in protein kinase C-␣ expression and phosphorylation of extracellular signal-regulated kinase 1/2, signal transducer and activator of transcription 3, Akt, and glycogen synthase kinase 3␤ were normalized by irbesartan and Ang 1-7. Ang receptor blocker and Ang 1-7 effectively reduced matrix metalloproteinase 2 activation and matrix metalloproteinase 9 levels. Ang II-mediated cellular effects in cultured adult cardiomyocytes and cardiofibrolasts isolated from pressure-overloaded ACE2-null hearts were inhibited to similar degree by AT 1 R blockade and stimulation with Ang 1-7. Thus, treatment with the AT 1 R blocker irbesartan and Ang 1-7 prevented the cardiac hypertrophy and improved cardiac remodeling in pressure-overloaded ACE2-null mice by suppressing NADPH oxidase and normalizing pathological signaling pathways. Key Words: renin-angiotensin system Ⅲ angiotensin 1-7 Ⅲ angiotensin-converting enzyme 2 Ⅲ NADPH oxidase Ⅲ AT 1 receptor Ⅲ heart failure Ⅲ signaling S everal lines of experimental and clinical evidence implicate a key role for the renin-angiotensin system in the pathophysiology of a number of cardiovascular diseases, such as myocardial infarction, hypertension, and heart failure. 1,2Angiotensin II (Ang II), acting via the Ang II type 1 receptor (AT 1 R) and Ang II type 2 receptor, modulates production of reactive oxygen species (ROS), impairing myocardial contractility and extracellular matrix remodeling, thereby negatively impacting on heart function.3 Angiotensin-converting enzyme 2 (ACE2), a homologue of angiotensin-converting enzyme, is a monocarboxypeptidase that metabolizes Ang II to yield angiotensin 1-7 (Ang 1-7) and lowers the Ang II/Ang 1-7 ratio.4-9 Ang II receptor blockers that selectively antagonize the AT 1 R became a valid alternative approach to interfere with the renin-angiotensin system axis and also upregulates ACE2, resulting in the generation of Ang 1-7. 10,11 Ang 1-7 acts on the Mas receptor and plays an important role in counteracting the actions of Ang II. 12-18Ang II-mediated oxidative stress, cardiac hypertrophy, contractile dysfunction, and fibrosis are exacerbated in ACE2-deficient mice, 5,7 whereas recombinant ...

A 3D computational model was developed to study the flow and the transport and deposition of nano-size particle in a realistic human nasal passage. The nasal cavity was constructed from a series of MRI images of coronal sections of a nose of a live human subject. For several breathing rates associated with low or moderate activities, the steady state flows in the nasal passage were simulated numerically. The airflow simulation results were compared with the available experimental data for the nasal passage. Despite the anatomical differences of the human subjects used in the experiments and computer model, the simulation results were in qualitative agreement with the experimental data.Deposition and transport of ultrafine particles (1 to 100 nm) in the nasal cavity for different breathing rates were also simulated using an Eulerian-Lagrangian approach. The simulation results for the nasal capture efficiency were found to be in reasonable agreement with the available experimental data for a number of human subjects given typical anatomical differences. The computational results for the nasal capture efficiency for nano-particles and various breathing rates in the laminar regime were found to correlate well with the ratio of particle diffusivity to the breathing rate especially for the particles smaller than 20 nm. Based on the simulated results, a semi-empirical equation for the capture efficiency of the nasal passage for nano-size particles was fitted in terms of Peclet number.

No abstract

BackgroundVarious pathways have been implicated in the pathogenesis of heart failure (HF) with preserved ejection fraction (HFPEF). Inflammation in response to comorbid conditions, such as hypertension and diabetes, may play a proportionally larger role in HFPEF as compared to HF with reduced ejection fraction (HFREF).Methods and ResultsThis study investigated inflammation mediated by the tumor necrosis factor-alpha (TNFα) axis in community-based cohorts of HFPEF patients (n = 100), HFREF patients (n = 100) and healthy controls (n = 50). Enzyme-linked immunosorbent assays were used to investigate levels of TNFα, its two receptors (TNFR1 and TNFR2), and a non-TNFα cytokine, interleukin-6 (IL-6), in plasma derived from peripheral blood samples. Plasma levels of TNFα and TNFR1 were significantly elevated in HFPEF relative to controls, while levels of TNFR2 were significantly higher in HFPEF than both controls and HFREF. TNFα, TNFR1 and TNFR2 were each significantly associated with at least two of the following: age, estimated glomerular filtration rate, hypertension, diabetes, smoking, peripheral vascular disease or history of atrial fibrillation. TNFR2 levels were also significantly associated with increasing grade of diastolic dysfunction and severity of symptoms in HFPEF.ConclusionsInflammation mediated through TNFα and its receptors, TNFR1 and TNFR2, may represent an important component of a comorbidity-induced inflammatory response that partially drives the pathophysiology of HFPEF.