Brain natriuretic peptide decreases pulmonary artery pressure in rats with pulmonary hypertension

Abstract only availableINTRODUCTION: B-type or Brain natriuretic peptide (BNP) was first isolated from the porcine brain, but it is primarily secreted from the cardiac ventricles in humans. As a cardiac hormone it has a physiologic regulatory function in the cardiovascular system. Along with atrial, and C-type natriuretic peptides, BNP aids in the natriuretic, diuretic, and vasorelaxant responses intended to reduce blood pressure and fluid volume homeostasis. Its vasodilator properties are known to be present in the pulmonary circulation; therefore, we hypothesized that BNP can be used as a therapy to lower the pulmonary artery pressure in an animal model of pulmonary hypertension. METHODS: Male Sprague-Dawley rats were given a one-time subcutaneous injection of 60 mg/kg monocrotaline to induce PH over a five week period. After establishment of PH, rats were anesthetized and ventilated. A catheter was placed in the right jugular vein and passed into the right ventricle to record right ventricular pressure (RVSP), an estimate of pulmonary artery pressure. A second catheter was placed in the right carotid artery to measure mean arterial pressure (MAP). RVSP and MAP were recorded before, during, and after infusions of BNP. RESULTS: One hour infusions of 5, 25, 50 or 150 ng/kg min BNP caused 24, 31 38, or 36% decreases in RVSP, respectively. There was no evidence of systemic hypotension at these doses of BNP. CONCLUSION: These preliminary findings suggest that BNP causes dose dependent decreases in pulmonary artery pressure in rats with pulmonary hypertension. Further study is needed to confirm these preliminary results.Louis Stokes Missouri Alliance for Minority Participatio

Ultrastructure study of the transgenic REN2 rat aorta – part 2: media, external elastic lamina, and adventitia

BackgroundThe renin-angiotensin-aldosterone system (RAAS) plays an important role in the development and progression of vascular stiffness, hypertension and accelerated atherosclerosis, which are associated with the metabolic syndrome (MetS) and type 2 diabetes mellitus. In addition to the intima, RAAS plays an important role in vascular media and adventitial remodeling. Methods Descending thoracic aortas of young male transgenic heterozygous (mRen2) 27 (Ren2) rats were utilized for ultrastructural study. This lean model of hypertension, insulin resistance, and oxidative stress harbors the mouse renin gene and is known to have increased aortic tissue levels of angiotensin II, angiotensin type 1 receptors, and elevated plasma aldosterone levels. ResultsUltrastructural observations substantiate known and novel findings in the tunica media, internal and external elastic lamina, and tunica adventitia, which includes: increased media collagen - proteoglycan matrix expansion, increased secretory and proliferative activity and migration of vascular smooth muscle cells (VSMCs) into a newly developing subendothelial neointima, increased VSMC caveolae, mitochondria degeneration, apoptosis; and lipid retention at the elastin lamellar interface. Openings in the external elastic lamina allow pericyte-to-VSMC contacts. The tunica adventitia exhibits stromal pericyte hyperplasia with actively synthetic phenotype and pericyte-pericyte connections. ConclusionWhile these studies only represent a single snapshot in time, they provide an evaluation of early abnormal ultrastructural vascular remodeling in Ren-2 models of the conduit-elastic thoracic aorta

Intrapulmonary expression of PPAR in a rat model of pulmonary hypertension [abstract]

Abstract only availableFaculty Mentor: Jeffrey Skimming MD and Vincent DeMarco PhD, Child HealthActivation of peroxisome proliferator-activated receptor-gamma (PPARγ) inhibits vascular smooth muscle proliferation and neointimal formation associated with pulmonary hypertension. Recently, our laboratory developed a model of pulmonary hypertension incorporating both pnuemonectomy (PNX) of the left lung and exposure to monocrotaline (MCT) in rats. Together, PNX and MCT caused inflammation and vascular remodeling within the right lung including smooth muscle proliferation and neointimal formation. Therefore, we tested the hypothesis that PNX/MCT dual insult induces pulmonary hypertension by decreasing PPARγ expression. METHODS: Sixteen rats were randomly divided into four groups: 1) PNX/MCT, 2) PNX/Phosphate Buffer Solution (PBS), 3) Sham Surgery (SS)/MCT, and 4) SS/PBS. Seven days after surgery, we injected the animals with either monocrotaline (60 mg/kg, s.q.) or PBS. Three weeks after those injections, right ventricular systolic pressures (RVSP) were measured. Lung tissue was harvested for analysis of PPARγ protein expression and histopathology. Right ventricular to left ventricular plus septum ratios (RVR) were also determined. RESULTS: PNX/MCT animals exhibited higher RVSPs and RVRs than the other treatment groups. Also, morphometric analysis revealed medial hypertrophy and neointimal formation within the resistance vessels of PNX/MCT rat lungs. In our study, neither PNX nor MCT alone had an effect on intrapulmonary expression of PPARγ protein. Surprisingly, however, the dual insult induced PPARγ expression (

Differential Regulation of Cardiac Function and Intracardiac Cytokines by Rapamycin in Healthy and Diabetic Rats

Diabetes is comorbid with cardiovascular disease and impaired immunity. Rapamycin improves cardiac functions and extends lifespan by inhibiting the mechanistic target of rapamycin complex 1 (mTORC1). However, in diabetic murine models, Rapamycin elevates hyperglycemia and reduces longevity. Since Rapamycin is an immunosuppressant, we examined whether Rapamycin (750 μg/kg/day) modulates intracardiac cytokines, which affect the cardiac immune response, and cardiac function in male lean (ZL) and diabetic obese Zucker (ZO) rats. Rapamycin suppressed levels of fasting triglycerides, insulin, and uric acid in ZO but increased glucose. Although Rapamycin improved multiple diastolic parameters (E/E′, E′/A′, E/Vp) initially, these improvements were reversed or absent in ZO at the end of treatment, despite suppression of cardiac fibrosis and phosphoSer473Akt. Intracardiac cytokine protein profiling and Ingenuity® Pathway Analysis indicated suppression of intracardiac immune defense in ZO, in response to Rapamycin treatment in both ZO and ZL. Rapamycin increased fibrosis in ZL without increasing phosphoSer473Akt and differentially modulated anti-fibrotic IL-10, IFNγ, and GM-CSF in ZL and ZO. Therefore, fundamental difference in intracardiac host defense between diabetic ZO and healthy ZL, combined with differential regulation of intracardiac cytokines by Rapamycin in ZO and ZL hearts, underlies differential cardiac outcomes of Rapamycin treatment in health and diabetes

Nebivolol, a beta adrenergic receptor antagonist blocks angiotensin II-mediated signaling in heart [abstract]

We recently showed that Nebivolol, a [beta]-adrenergic receptor (AR) antagonist attenuates myocardial oxidative stress and promotes insulin metabolic signaling in 9 week old Zucker obese (ZO) insulin resistant rats. Here, we demonstrate that Nebivolol suppresses angiotensin II type I receptor (AT1R)-mediated signaling in ZO hearts as well as in HL-1 cardiomyocytes

Suppression of Inflammatory Cardiac Cytokine Network in Rats with Untreated Obesity and Pre-Diabetes by AT2 Receptor Agonist NP-6A4

Obesity affects over 42% of the United States population and exacerbates heart disease, the leading cause of death in men and women. Obesity also increases pro-inflammatory cytokines that cause chronic tissue damage to vital organs. The standard-of-care does not sufficiently attenuate these inflammatory sequelae. Angiotensin II receptor AT2R is an anti-inflammatory and cardiovascular protective molecule; however, AT2R agonists are not used in the clinic to treat heart disease. NP-6A4 is a new AT2R peptide agonist with an FDA orphan drug designation for pediatric cardiomyopathy. NP-6A4 increases AT2R expression (mRNA and protein) and nitric oxide generation in human cardiovascular cells. AT2R-antagonist PD123319 and AT2RSiRNA suppress NP-6A4-effects indicating that NP-6A4 acts through AT2R. To determine whether NP-6A4 would mitigate cardiac damage from chronic inflammation induced by untreated obesity, we investigated the effects of 2-weeks NP-6A4 treatment (1.8 mg/kg delivered subcutaneously) on cardiac pathology of male Zucker obese (ZO) rats that display obesity, pre-diabetes and cardiac dysfunction. NP-6A4 attenuated cardiac diastolic and systolic dysfunction, cardiac fibrosis and cardiomyocyte hypertrophy, but increased myocardial capillary density. NP-6A4 treatment suppressed tubulointerstitial injury marker urinary β-NAG, and liver injury marker alkaline phosphatase in serum. These protective effects of NP-6A4 occurred in the presence of obesity, hyperinsulinemia, hyperglycemia, and hyperlipidemia, and without modulating blood pressure. NP-6A4 increased expression of AT2R (consistent with human cells) and cardioprotective erythropoietin (EPO) and Notch1 in ZO rat heart, but suppressed nineteen inflammatory cytokines. Cardiac miRNA profiling and in silico analysis showed that NP-6A4 activated a unique miRNA network that may regulate expression of AT2R, EPO, Notch1 and inflammatory cytokines, and mitigate cardiac pathology. Seventeen pro-inflammatory and pro-fibrotic cytokines that increase during lethal cytokine storms caused by infections such as COVID-19 were among the cytokines suppressed by NP-6A4 treatment in ZO rat heart. Thus, NP-6A4 activates a novel anti-inflammatory network comprised of 21 proteins in the heart that was not reported previously. Since NP-6A4’s unique mode of action suppresses pro-inflammatory cytokine network and attenuates myocardial damage, it can be an ideal adjuvant drug with other anti-glycemic, anti-hypertensive, standard-of-care drugs to protect the heart tissues from pro-inflammatory and pro-fibrotic cytokine attack induced by obesity

Combination Therapy of Brain Natriuretic Peptide and Sildenafil Attenuates Pulmonary Hypertension in Rats [abstract]

Abstract only availableFaculty Mentor: Dr. Vincent DeMarco, Child HealthBackground: Pulmonary arterial hypertension (PAH) is a lethal disease characterized by changes in pulmonary vascular structure and function. We tested the hypothesis that Sildenafil, a phosphodiesterase 5 inhibitor, and brain natriuretic peptide (BNP), a guanosine cyclase stimulator, in combination synergistically attenuates PAH when compared to individual therapy in rats through different mechanisms to increase cGMP while minimizing systemic side effects. Methods: Adult male Sprague-Dawley rats were subcutaneously injected with monocrotaline (n=30, 50 mg/kg). After approximately 5 weeks, rats were anesthetized and instrumented to measure systemic pressure (MAP) and right ventricular systolic pressure (RVSP) during infusions of vehicle solution (n=5), intravenous Sildenafil (84 mg/kg/min; n=8), and intravenous BNP (100 ng/kg/min; n=7) alone and a combination of Sildenafil and BNP (n=10). Results: Sildenafil alone decreased RVSP (-17 ±13.2 mmHg) and had a relatively minimal effect on MAP (-4±9.9 mmHg). BNP decreased RVSP (-19±14 mmHg) but also significantly effected MAP (-11±15.3mmHg). Combination therapy with Sildenafil and BNP lowered RVSP (-20±18.7 mmHg), however it also induced the greatest systemic hypotensive effect (MAP = -19±9.9 mmHg). Conclusion: The combination of Sildenafil and BNP, at these doses, significantly attenuates monocrotaline-induced pulmonary hypertension. However, compared with individual treatment, there is no significant difference in effect on RVSP. Furthermore, additive systemic side effects are too significant to consider combination therapy safe. With a different dosing regime, this combination is a potentially viable option in the treatment of patients with PAH

The SGLT2 inhibitor Empagliflozin attenuates interleukin-17A-induced human aortic smooth muscle cell proliferation and migration by targeting TRAF3IP2/ROS/NLRP3/Caspase-1-dependent IL-1β and IL-18 secretion

Chronic inflammation and persistent oxidative stress contribute to the development and progression of vascular proliferative diseases. We hypothesized that the proinflammatory cytokine interleukin (IL)-17A induces oxidative stress and amplifies inflammatory signaling in human aortic smooth muscle cells (SMC) via TRAF3IP2-mediated NLRP3/caspase-1-dependent mitogenic and migratory proinflammatory cytokines IL-1β and IL-18. Further, we hypothesized that these maladaptive changes are prevented by empagliflozin (EMPA), an SGLT2 (Sodium/Glucose Cotransporter 2) inhibitor. Supporting our hypotheses, exposure of cultured SMC to IL-17A promoted proliferation and migration via TRAF3IP2, TRAF3IP2-dependent superoxide and hydrogen peroxide production, NLRP3 expression, caspase-1 activation, and IL-1β and IL-18 secretion. Furthermore, NLRP3 knockdown, caspase-1 inhibition, and pretreatment with IL-1β and IL-18 neutralizing antibodies and IL-18BP, each attenuated IL-17A-induced SMC migration and proliferation. Importantly, SMC express SGLT2, and pre-treatment with EMPA attenuated IL-17A/TRAF3IP2-dependent oxidative stress, NLRP3 expression, caspase-1 activation, IL-1β and IL-18 secretion, and SMC proliferation and migration. Importantly, silencing SGLT2 attenuated EMPA-mediated inhibition of IL-17A-induced cytokine secretion and SMC proliferation and migration. EMPA exerted these beneficial antioxidant, anti-inflammatory, anti-mitogenic and anti-migratory effects under normal glucose conditions and without inducing cell death. These results suggest the therapeutic potential of EMPA in vascular proliferative diseases

Anderson localization in Bose-Einstein condensates

The understanding of disordered quantum systems is still far from being complete, despite many decades of research on a variety of physical systems. In this review we discuss how Bose-Einstein condensates of ultracold atoms in disordered potentials have opened a new window for studying fundamental phenomena related to disorder. In particular, we point our attention to recent experimental studies on Anderson localization and on the interplay of disorder and weak interactions. These realize a very promising starting point for a deeper understanding of the complex behaviour of interacting, disordered systems.Comment: 15 pages review, to appear in Reports on Progress in Physic

Mineralocorticoid receptor antagonism attenuates vascular apoptosis and injury via rescuing protein kinase B activation

This article may also be found at the publisher's website at http://hyper.ahajournals.org/cgi/content/abstract/53/2/158?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=habibi&searchid=1&FIRSTINDEX=0&resourcetype=HWCITEmerging evidence indicates that mineralocorticoid receptor (MR) blockade reduces the risk of cardiovascular events beyond those predicted by its blood pressure-lowering actions; however, the underlying mechanisms remain unclear. To investigate whether protection elicited by MR blockade is through attenuation of vascular apoptosis and injury, independently of blood pressure lowering, we administered a low dose of the MR antagonist spironolactone or vehicle for 21 days to hypertensive transgenic Ren2 rats with elevated plasma aldosterone levels. Although Ren2 rats developed higher systolic blood pressures compared with Sprague-Dawley littermates, low-dose spironolactone treatment did not reduce systolic blood pressure compared with untreated Ren2 rats. Ren2 rats exhibited vascular injury as evidenced by increased apoptosis, hemidesmosome-like structure loss, mitochondrial abnormalities, and lipid accumulation compared with Sprague-Dawley rats, and these abnormalities were attenuated by MR antagonism. Protein kinase B activation is critical to vascular homeostasis via regulation of cell survival and expression of apoptotic genes. Protein kinase B serine473 phosphorylation was impaired in Ren2 aortas and restored with MR antagonism. In vivo MR antagonist treatment promoted antiapoptotic effects by increasing phosphorylation of BAD serine136 and expression of Bcl-2 and Bcl-xL, decreasing cytochrome c release and BAD expression, and suppressing caspase-3 activation. Furthermore, MR antagonism substantially reduced the elevated NADPH oxidase activity and lipid peroxidation, expression of angiotensin II, angiotensin type 1 receptor, and MR in Ren2 vasculature. These results demonstrate that MR antagonism protects the vasculature from aldosterone-induced vascular apoptosis and structural injury via rescuing protein kinase B activation, independent of blood pressure effects