Complementary Embryonic and Adult Cell Populations Enhance Myocardial Repair in Rat Myocardial Injury Model.

We compared the functional outcome of Isl-1 cardiac progenitors, CD90 bone marrow-derived progenitor cells, and the combination of the two in a rat myocardial infarction (MI) model. Isl-1 cells were isolated from embryonic day 12.5 (E12.

Involvement of Neuroinflammation in the Pathogenesis of Monocrotaline-Induced Pulmonary Hypertension.

Pulmonary hypertension (PH) is a devastating disease and its successful treatment remains to be accomplished despite recent advances in pharmacotherapy. It has been proposed that PH be considered as a systemic disease, rather than primarily a disease of the pulmonary vasculature. Consequently, an investigation of the intricate interplay between multiple organs such as brain, vasculature, and lung in PH could lead to the identification of new targets for its therapy.

The Selective Angiotensin II Type 2 Receptor Agonist, Compound 21, Attenuates the Progression of Lung Fibrosis and Pulmonary Hypertension in an Experimental Model of Bleomycin-Induced Lung Injury.

Idiopathic Pulmonary Fibrosis (IPF) is a chronic lung disease characterized by scar formation and respiratory insufficiency, which progressively leads to death. Pulmonary hypertension (PH) is a common complication of IPF that negatively impacts clinical outcomes, and has been classified as Group III PH. Despite scientific advances, the dismal prognosis of IPF and associated PH remains unchanged, necessitating the search for novel therapeutic strategies.

Coupling corticotropin-releasing-hormone and angiotensin converting enzyme 2 dampens stress responsiveness in male mice.

This study used mice to evaluate whether coupling expression of corticotropin-releasing hormone (CRH) and angiotensin converting enzyme 2 (ACE2) creates central interactions that blunt endocrine and behavioral responses to psychogenic stress. Central administration of diminazene aceturate, an ACE2 activator, had no effect on restraint-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis; however, mice that ubiquitously overexpress ACE2 had reduced plasma corticosterone (CORT) and pituitary expression of POMC mRNA. The Cre-LoxP system was used to restrict ACE2 overexpression to CRH synthesizing cells and probe whether HPA axis suppression was the result of central ACE2 and CRH interactions.

Beneficial Effects of Angiotensin-(1-7) on CD34+ Cells From Patients With Heart Failure.

The dysfunctional nature of CD34 cells from patients with heart failure (HF) may make them unsuitable for autologous stem-cell therapy. In view of evidence that the vasoprotective axis of the renin-angiotensin system (RAS) improves CD34 cell functions, we hypothesized that CD34 cells from patients with HF will be dysfunctional and that angiotensin-(1-7) [Ang-(1-7)] would improve their function. Peripheral blood was collected from New York Heart Association class II-IV patients with HF (n = 31) and reference subjects (n = 16).

Therapeutic potential of adipose stem cell-derived conditioned medium against pulmonary hypertension and lung fibrosis.

Background And Purpose: Pulmonary hypertension (PH) and pulmonary fibrosis (PF) are life threatening cardiopulmonary diseases. Existing pharmacological interventions have failed to improve clinical outcomes or reduce disease-associated mortality. Emerging evidence suggests that stem cells offer an effective treatment approach against various pathological conditions.

Increasing brain angiotensin converting enzyme 2 activity decreases anxiety-like behavior in male mice by activating central Mas receptors.

Over-activation of the brain renin-angiotensin system (RAS) has been implicated in the etiology of anxiety disorders. Angiotensin converting enzyme 2 (ACE2) inhibits RAS activity by converting angiotensin-II, the effector peptide of RAS, to angiotensin-(1-7), which activates the Mas receptor (MasR). Whether increasing brain ACE2 activity reduces anxiety by stimulating central MasR is unknown.

Angiotensin-(1-7) Decreases Cell Growth and Angiogenesis of Human Nasopharyngeal Carcinoma Xenografts.

Angiotensin-(1-7) [Ang-(1-7)] is an endogenous, heptapeptide hormone acting through the Mas receptor (MasR), with antiproliferative and antiangiogenic properties. Recent studies have shown that Ang-(1-7) has an antiproliferative action on lung adenocarcinoma cells and prostate cancer cells. In this study, we report that MasR levels were significantly upregulated in nasopharyngeal carcinoma (NPC) specimens and NPC cell lines.

Angiotensin-converting enzyme 2 inhibits high-mobility group box 1 and attenuates cardiac dysfunction post-myocardial ischemia.

High-mobility group box 1 (HMGB1) triggers and amplifies inflammation cascade following ischemic injury, and its elevated levels are associated with adverse clinical outcomes in patients with myocardial infarction (MI). Angiotensin-converting enzyme 2 (ACE2), a key member of vasoprotective axis of the renin-angiotensin system (RAS), regulates cardiovascular functions and exerts beneficial effects in cardiovascular disease. However, the association between HMGB1 and ACE2 has not been studied.

ACE2 and Microbiota: Emerging Targets for Cardiopulmonary Disease Therapy.

The health of the cardiovascular and pulmonary systems is inextricably linked to the renin-angiotensin system (RAS). Physiologically speaking, a balance between the vasodeleterious (Angiotensin-converting enzyme [ACE]/Angiotensin II [Ang II]/Ang II type 1 receptor [AT1R]) and vasoprotective (Angiotensin-converting enzyme 2 [ACE2]/Angiotensin-(1-7) [Ang-(1-7)]/Mas receptor [MasR]) components of the RAS is critical for cardiopulmonary homeostasis. Upregulation of the ACE/Ang II/AT1R axis shifts the system toward vasoconstriction, proliferation, hypertrophy, inflammation, and fibrosis, all factors that contribute to the development and progression of cardiopulmonary diseases.

Oral delivery of Angiotensin-converting enzyme 2 and Angiotensin-(1-7) bioencapsulated in plant cells attenuates pulmonary hypertension.

Emerging evidences indicate that diminished activity of the vasoprotective axis of the renin-angiotensin system, constituting angiotensin-converting enzyme 2 (ACE2) and its enzymatic product, angiotensin-(1-7) [Ang-(1-7)] contribute to the pathogenesis of pulmonary hypertension (PH). However, long-term repetitive delivery of ACE2 or Ang-(1-7) would require enhanced protein stability and ease of administration to improve patient compliance. Chloroplast expression of therapeutic proteins enables their bioencapsulation within plant cells to protect against gastric enzymatic degradation and facilitates long-term storage at room temperature.

Neuroinflammation in pulmonary hypertension: concept, facts, and relevance.

Pulmonary hypertension (PH) is a progressive lung disease characterized by elevated pressure in the lung vasculature, resulting in right-sided heart failure and premature death. The pathogenesis of PH is complex and multifactorial, involving a dysregulated autonomic nervous system and immune response. Inflammatory mechanisms have been linked to the development and progression of PH; however, these are usually restricted to systemic and/or local lung tissue.

The angiotensin type 2 receptor agonist Compound 21 elicits cerebroprotection in endothelin-1 induced ischemic stroke.

Evidence indicates that angiotensin II type 2 receptors (AT2R) exert cerebroprotective actions during stroke. A selective non-peptide AT2R agonist, Compound 21 (C21), has been shown to exert beneficial effects in models of cardiac and renal disease, as well as hemorrhagic stroke. Here, we hypothesize that C21 may exert beneficial effects against cerebral damage and neurological deficits produced by ischemic stroke.

Diminazene aceturate enhances angiotensin-converting enzyme 2 activity and attenuates ischemia-induced cardiac pathophysiology.

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. Diminazene aceturate (DIZE), a small molecule ACE2 activator, has been used to evaluate this hypothesis.

Diminazene aceturate improves autonomic modulation in pulmonary hypertension.

We have previously demonstrated that diminazene aceturate (DIZE), a putative angiotensin 1-7 converting enzyme activator, protects rats from monocrotaline (MCT)-induced pulmonary hypertension (PH). The present study was conducted to determine if the beneficial effects of DIZE are associated with improvements in autonomic nervous system (ANS) modulation. PH was induced in male rats by a single subcutaneous injection of MCT (50 mg/kg).

Angiotensin-converting enzyme 2 activation improves endothelial function.

Diminished release and function of endothelium-derived nitric oxide coupled with increases in reactive oxygen species production is critical in endothelial dysfunction. Recent evidences have shown that activation of the protective axis of the renin-angiotensin system composed by angiotensin-converting enzyme 2, angiotensin-(1-7), and Mas receptor promotes many beneficial vascular effects. This has led us to postulate that activation of intrinsic angiotensin-converting enzyme 2 would improve endothelial function by decreasing the reactive oxygen species production.

Chronic knockdown of the nucleus of the solitary tract AT1 receptors increases blood inflammatory-endothelial progenitor cell ratio and exacerbates hypertension in the spontaneously hypertensive rat.

AT1 receptor subtype a (AT1Ra) expression is increased in the nucleus of the solitary tract (NTS) in spontaneously hypertensive rat (SHR) compared with Wistar Kyoto controls. However, the chronic role of AT1Ra in the NTS for cardiovascular control is not well understood. In this study, we investigated the hypothesis that the NTS AT1Ra is involved in the neural regulation of the peripheral inflammatory status and linked with hypertension.

Diminazene attenuates pulmonary hypertension and improves angiogenic progenitor cell functions in experimental models.

Rationale: Studies have demonstrated that angiotensin-converting enzyme 2 (ACE2) plays a protective role against lung diseases, including pulmonary hypertension (PH). Recently, an antitrypanosomal drug, diminazene aceturate (DIZE), was shown to exert an "off-target" effect of enhancing the enzymatic activity of ACE2 in vitro.

Objectives: To evaluate the pharmacological actions of DIZE in experimental models of PH.

Comparison of the transduction efficiency of tyrosine-mutant adeno-associated virus serotype vectors in kidney.

Gene therapy has a distinct potential to treat kidney diseases. However, the efficient transduction of a significant number of renal cells by viral vectors has been difficult to accomplish. Previous studies indicate that adeno-associated virus (AAV) can transduce renal cells with variable and suboptimal efficiency.

Oral administration of an angiotensin-converting enzyme 2 activator ameliorates diabetes-induced cardiac dysfunction.

We evaluated the hypothesis that activation of endogenous angiotensin-converting enzyme (ACE) 2 would improve cardiac dysfunction induced by diabetes. Ten days after diabetes induction (streptozotocin, 50 mg/kg, i.v.

Moderate cardiac-selective overexpression of angiotensin II type 2 receptor protects cardiac functions from ischaemic injury.

We hypothesized that moderate cardiac-selective overexpression of the angiotensin II type 2 receptor (AT2R) would protect the myocardium from ischaemic injury after a myocardial infarction (MI) induced by coronary artery ligation. For in vitro studies, adenoviral vector expressing genomic DNA of AT2R and enhanced green fluorescence protein (EGFP) was used to overexpress AT2R in rat neonatal cardiac myocytes. Expression of AT2R, measured by real-time PCR and immunostaining, demonstrated efficient transduction of AT2R in a dose-dependent pattern.

Lentivirus-mediated overexpression of angiotensin-(1-7) attenuated ischaemia-induced cardiac pathophysiology.

Myocardial infarction (MI) results in cell death, development of interstitial fibrosis, ventricular wall thinning and ultimately, heart failure. Angiotensin-(1-7) [Ang-(1-7)] has been shown to provide cardioprotective effects. We hypothesize that lentivirus-mediated overexpression of Ang-(1-7) would protect the myocardium from ischaemic injury.

Cerebroprotection by angiotensin-(1-7) in endothelin-1-induced ischaemic stroke.

Activation of angiotensin-converting enzyme 2 (ACE2), production of angiotensin-(1-7) [Ang-(1-7)] and stimulation of the Ang-(1-7) receptor Mas exert beneficial actions in various peripheral cardiovascular diseases, largely through opposition of the deleterious effects of angiotensin II via its type 1 receptor. Here we considered the possibility that Ang-(1-7) may exert beneficial effects against CNS damage and neurological deficits produced by cerebral ischaemic stroke. We determined the effects of central administration of Ang-(1-7) or pharmacological activation of ACE2 on the cerebral damage and behavioural deficits elicited by endothelin-1 (ET-1)-induced middle cerebral artery occlusion (MCAO), a model of cerebral ischaemia.

ACE2, a promising therapeutic target for pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a chronic lung disease with poor diagnosis and limited therapeutic options. The currently available therapies are ineffective in improving the quality of life and reducing mortality rates. There exists a clear unmet medical need to treat this disease, which necessitates the discovery of novel therapeutic targets/agents for safe and successful therapy.