Hypertension Editors' Picks: Novel Drugs.

Abstract

HomeHypertensionVol. 75, No. 6Hypertension Editors’ Picks Free AccessNewsPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessNewsPDF/EPUBHypertension Editors’ PicksNovel Drugs The Editors The Editors Search for more papers by this author Originally published13 May 2020https://doi.org/10.1161/HYPERTENSIONAHA.120.15200Hypertension. 2020;75:e17–e28The following articles on new drug-based approaches to treating hypertension are highlighted as part of Hypertension’s Editors’ Picks series. Notwithstanding the large number and variety of drugs currently available to the clinician for managing hypertension, overall control of hypertension remains suboptimal world wide, but especially in low-middle-income countries. This can be ascribed to following 3 factors: (1) most patients require drug therapy—not merely lifestyle changes—to reach desired blood pressure targets; (2) a large number of patients do not reliably adhere to prescribed antihypertensive drug regimens; and (3) a significant fraction of patients with hypertension fail to reach target blood pressures even when taking 5 or more antihypertensive drugs from different classes. While device-based therapies may offer some remedy, it is likely that only small numbers of select patients can be managed using such approaches. Improved patient education, communication, and support strategies aimed at encouraging adherence to prescribed drug treatments are certain to impact a greater number of patients. But even after considering these approaches, the need remains for discovery and introduction into clinical practice of new drugs that can chronically lower arterial pressure while producing few or no significant adverse effects. Given the common requirement for combination therapy in managing hypertension, it is particularly desirable that such agents lower arterial pressure via novel mechanisms so that their effects will be additive or even synergistic with existing drugs. Papers highlighted below identify many new molecular drug targets such as mammalian target of rapamycin, renal outer medullary potassium channels, Ca(2+)-activated Cl(−) channels, and protein kinase G Ialpha. Others describe drugs that interact in novel ways with more established pressure control pathways such as endothelial NO synthase, natriuretic peptides, cyclooxygenases or the renin angiotensin system. Another potential strategy for drug treatment of hypertension is to identify drugs that limit hypertensive damage to target organs without necessarily affecting blood pressure itself. Several papers describe such an approach, with the immune system emerging as a particularly promising target. Finally, it is worth noting that new drug development is not limited to the traditional small molecule route but includes vaccines and a variety of RNA-based platforms. Meaningful changes in our now long-standing pharmacological approach to the treatment of hypertension can be expected within the next few years.Evolution of a New Class of Antihypertensive Drugs: Targeting the Brain Renin-Angiotensin System1AbstractIn addition to the circulating renin-angiotensin system, activation of the brain renin-angiotensin system plays an important role in the pathophysiology of hypertension. One of the major components of the brain renin-angiotensin system implicated in the development of hypertension is Ang III (angiotensin III). Brain Ang III, produced from Ang II (angiotensin II) by APA (aminopeptidase A), exerts a tonic stimulatory control over blood pressure in hypertensive rats. Targeting Ang III by inhibiting brain APA is now considered a potentially important target in the management of hypertension. This has led to development of RB150, an orally active prodrug of the specific and selective APA inhibitor, EC33. Orally administered RB150 crosses the gastrointestinal and blood-brain barriers, enters the brain where it generates 2 active molecules of EC33 that block brain APA activity. This results in decreased brain Ang III formation and reduced blood pressure in hypertensive rats. The RB150-induced blood pressure decrease is due to a reduced vasopressin release, which increases diuresis, reducing extracellular volume, a decrease in sympathetic tone, leading to a reduction of vascular resistances, and the improvement of the baroreflex function. RB150 was renamed firibastat by the World Health Organization. Phase Ia/Ib clinical trials showed that firibastat is clinically and biologically well tolerated in healthy volunteers. Clinical efficacy of firibastat in hypertensive patients was, therefore, demonstrated in 2 phase II studies. Accordingly, firibastat could represent the first drug of a novel class of antihypertensive drugs targeting the brain renin-angiotensin system.Strong and Sustained Antihypertensive Effect of Small Interfering RNA Targeting Liver Angiotensinogen2AbstractSmall interfering RNAs (siRNAs) targeting hepatic angiotensinogen (Agt) may provide long-lasting antihypertensive effects, but the optimal approach remains unclear. Here, we assessed the efficacy of a novel AGT siRNA in spontaneously hypertensive rats. Rats were treated with vehicle, siRNA (10 mg/kg fortnightly; subcutaneous), valsartan (31 mg/kg per day; oral), captopril (100 mg/kg per day; oral), valsartan+siRNA, or captopril+valsartan for 4 weeks (all groups, n=8). Mean arterial pressure (recorded via radiotelemetry) was lowered the most by valsartan+siRNA (−68±4 mm Hg), followed by captopril+valsartan (−54±4 mm Hg), captopril (−23±2 mm Hg), siRNA (−14±2 mm Hg), and valsartan (−10±2 mm Hg). siRNA and captopril monotherapies improved cardiac hypertrophy equally, but less than the dual therapies, which also lowered NT-proBNP (N-terminal pro-B-type natriuretic peptide). Glomerular filtration rate, urinary NGAL (neutrophil gelatinase-associated lipocalin), and albuminuria were unaffected by treatment. siRNA lowered circulating AGT by 97.9±1.0%, and by 99.8±0.1% in combination with valsartan. Although siRNA greatly reduced renal Ang (angiotensin) I, only valsartan+siRNA suppressed circulating and renal Ang II. This coincided with decreased renal sodium hydrogen exchanger type 3 and phosphorylated sodium chloride cotransporter abundances. Renin and plasma K(+) increased with every treatment, but especially during valsartan+siRNA; no effects on aldosterone were observed. Collectively, these data indicate that Ang II elimination requires >99% suppression of circulating AGT. Maximal blockade of the renin-angiotensin system, achieved by valsartan+siRNA, yielded the greatest reduction in blood pressure and cardiac hypertrophy, whereas AGT lowering alone was as effective as conventional renin-angiotensin system inhibitors. Given its stable and sustained efficacy, lasting weeks, RNA interference may offer a unique approach to improving therapy adherence and treating hypertension.Novel Role of T Cells and Interleukin-6 in Angiotensin II-Induced Microvascular Dysfunction3AbstractHypertension is an established risk factor for subsequent cardiovascular diseases, with Ang II (angiotensin II) playing a major role in mediating thrombotic and inflammatory abnormalities. Although T cells and IL-6 (interleukin-6) play an important role in adaptive immune responses, little is known about their role(s) in the thromboinflammatory responses associated with Ang II. Here, we show using intravital microscopy coupled with the light/dye injury model that Rag-1 deficient (Rag-1[−/−]) and IL-6 deficient (IL-6[−/−]) mice are afforded protection against Ang II-induced thrombosis. Blocking IL-6 receptors (using CD126 and gp130 antibodies) significantly diminished Ang II-mediated thrombosis and inflammatory cell recruitment in mice. Furthermore, the adoptive transfer of IL-6(−/−)-derived T cells into Rag-1(−/−) mice failed to accelerate Ang II-induced thrombosis compared with Rag-1(−/−) mice reconstituted with wild-type-derived T cells, suggesting that T cell IL-6 mediates the thrombotic abnormalities associated Ang II hypertension. Interestingly, adoptive transfer of WT T cells into Rag-1(−/−)/Ang II mice resulted in increased numbers of immature platelets, which constitutes a more active platelet population, that is, prothrombotic and proinflammatory. To translate our in vivo findings, we used clinical samples to demonstrate that IL-6 also predisposes platelets to an interaction with collagen receptors, thereby increasing the propensity for platelets to aggregate and cause thrombosis. In summary, we provide compelling evidence for the involvement of IL-6, IL-6R, and T-cell-dependent IL-6 signaling in Ang II-induced thromboinflammation, which may provide new therapeutic possibilities for drug discovery programs for the management of hypertension.Design, Synthesis, and Actions of an Innovative Bispecific Designer Peptide4AbstractDespite optimal current therapies, cardiovascular disease remains the leading cause for death worldwide. Importantly, advances in peptide engineering have accelerated the development of innovative therapeutics for diverse human disease states. Additionally, the advancement of bispecific therapeutics targeting >1 signaling pathway represents a highly innovative strategy for the treatment of cardiovascular disease. We, therefore, engineered a novel, designer peptide, which simultaneously targets the pGC-A (particulate guanylyl cyclase A) receptor and the MasR (Mas receptor), potentially representing an attractive cardiorenoprotective therapeutic for cardiovascular disease. We engineered a novel, bispecific receptor activator, NPA7, that represents the fusion of a 22-amino acid sequence of BNP (B-type natriuretic peptide; an endogenous ligand of pGC-A) with Ang 1-7 (angiotensin 1-7)-the 7-amino acid endogenous activator of MasR. We assessed NPA7’s dual receptor activating actions in vitro (second messenger production and receptor interaction). Further, we performed an intravenous peptide infusion comparison study in normal canines to study its biological actions in vivo, including in the presence of an MasR antagonist. Our in vivo and in vitro studies demonstrate the successful synthesis of NPA7 as a bispecific receptor activator targeting pGC-A and MasR. In normal canines, NPA7 possesses enhanced natriuretic, diuretic, systemic, and renal vasorelaxing and cardiac unloading properties. Importantly, NPA7’s actions are superior to that of the individual native pGC-A or MasR ligands. These studies advance NPA7 as a novel, bispecific designer peptide with potential cardiorenal therapeutic benefit for the treatment of cardiovascular disease, such as hypertension and heart failure.Shear-Sensitive lncRNA AF131217.1 Inhibits Inflammation in HUVECs via Regulation of KLF (Kruppel-Like Factor) 45AbstractAtherosclerosis is one of the most common vascular diseases, and inflammation participates in all stages of its progression. Laminar shear stress protects arteries from atherosclerosis and reduces endothelial inflammation. Long noncoding RNAs have emerged as critical regulators in many diseases, including atherosclerosis. However, the expression and functions of long noncoding RNAs subjected to laminar shear stress in endothelial cells remain unclear. This study aimed to reveal the mechanism by which shear stress–regulated long noncoding RNAs contribute to anti-inflammation. In this study, we identified a novel long noncoding RNA AF131217.1, which was upregulated after laminar shear stress treatment in human umbilical vein endothelial cells. Knockdown of AF131217.1 inhibited flow-mediated reduction of monocyte adhesion VCAM-1 (vascular cell adhesion molecule-1) and ICAM-1 (intercellular adhesion molecule-1) expression and inhibited flow-mediated enhancement of flow-responsive expression of KLF (Kruppel-like factor) 2 and eNOS (endothelial NO synthase). Furthermore, TNF-α (tumor necrosis factor-α) was used to induce an inflammatory response in human umbilical vein endothelial cells. Knockdown of AF131217.1 promoted ICAM-1 and VCAM-1 expression, as well as changes in monocyte adhesion and KLF2 and eNOS expression induced by TNF-α. Mechanistic investigations indicated that AF131217.1 acted as a competing endogenous RNA for miR-128-3p, leading to regulation of its target gene KLF4. In conclusion, our study demonstrates for the first time that laminar shear stress regulates the expression of AF131217.1 in human umbilical vein endothelial cells, and the AF131217.1/miR-128-3p/KLF4 axis plays a vital role in atherosclerosis development.MicroRNA-31 Regulates Immunosuppression in Ang II (Angiotensin II)-Induced Hypertension by Targeting Ppp6C (Protein Phosphatase 6c)6AbstractRegulatory T cells (Treg cells) play important roles in hypertension and organ damages. MicroRNA-31 (miR-31) is a critical regulator for Treg cell generation. However, the role of miR-31 in hypertension has not been elucidated. We aim to study the functionality of miR-31 and the detailed mechanism in Ang II (Angiotensin II)-induced hypertensive mouse model. We found: In vitro, miR-31 expression was higher in T helper 17 cells and lower in Treg cells than that of naive T cells. The genetic deficiency of miR-31 promoted Treg cell differentiation, whereas no impact on T helper 17 cells differentiation. Ang II-induced hypertension resulted in increased expression of miR-31 in the aorta, splenic CD4(+) T cells, and kidney leukocytes. MiR-31 deficiency strikingly decreased systolic blood pressure and diastolic blood pressure and attenuated renal and vascular damage. MiR-31 deletion altered the accumulation of Treg cells and macrophages and expression of inflammatory cytokines in kidneys in Ang II-induced hypertensive mice. Ang II treatment reduced the levels of anti-inflammatory cytokines and increased proinflammatory cytokines in plasma that were blunted by the miR-31 deletion. Ppp6C (protein phosphatase 6c; a direct target of miR-31) specific deletion in Treg cells led to marked impairment of Treg cell induction, increased Ang II-induced blood pressure elevation, and organ damage in mice. In conclusion, we provided novel evidence of miR-31 as an emerging key posttranscriptional regulator of hypertension-associated immunosuppression through targeting ppp6C, which is a critical regulator in the differentiation of Treg cells. This study offers new perspectives on miRNA-based therapeutic approaches.Novel Treatment of Hypertension by Specifically Targeting E2F for Restoration of Endothelial Dihydrofolate Reductase and eNOS (Endothelial NO Synthase) Function Under Oxidative Stress7AbstractWe have shown that hydrogen peroxide (H2O2) downregulates tetrahydrobiopterin salvage enzyme DHFR (dihydrofolate reductase) to result in eNOS (endothelial NO synthase) uncoupling and elevated blood pressure. Here, we aimed to delineate molecular mechanisms underlying H2O2 downregulation of endothelial DHFR by examining transcriptional pathways hypothesized to modulate DHFR expression and effects on blood pressure regulation of targeting these novel mechanisms. H2O2 dose and time dependently attenuated DHFR mRNA and protein expression and enzymatic activity in endothelial cells. Deletion of E2F-binding sites, but not those of Sp1 (specificity protein 1), abolished H2O2 attenuation of DHFR promoter activity. Overexpression of E2F1/2/3a activated DHFR promoter at baseline and alleviated the inhibitory effect of H2O2 on DHFR promoter activity. H2O2 treatment diminished mRNA and protein expression of E2F1/2/3a, whereas overexpression of E2F isoforms increased DHFR protein levels. Chromatin immunoprecipitation assay indicated direct binding of E2F1/2/3a to the DHFR promoter, which was weakened by H2O2. E2F1 RNA interference attenuated DHFR protein levels, whereas its overexpression elevated tetrahydrobiopterin levels and tetrahydrobiopterin/dihydrobiopterin ratios in vitro and in vivo. In Ang II (angiotensin II)-infused mice, adenovirus-mediated overexpression of E2F1 markedly abrogated blood pressure to control levels, by restoring endothelial DHFR function to improve NO bioavailability and vasorelaxation. Bioinformatic analyses confirmed a positive correlation between E2F1 and DHFR in human endothelial cells and arteries, and downregulation of both by oxidized phospholipids. In summary, endothelial DHFR is downregulated by H2O2 transcriptionally via an E2F-dependent mechanism, and that specifically targeting E2F1/2/3a to restore DHFR and eNOS function may serve as a novel therapeutic option for the treatment of hypertension.Mineralocorticoid Receptor Induces Adipose Tissue Senescence and Mitochondrial Dysfunction Leading to Vascular Dysfunction in Obesity8AbstractAdipose tissue (AT) senescence and mitochondrial dysfunction are associated with obesity. Studies in obese patients and animals demonstrate that the MR (mineralocorticoid receptor) contributes to obesity-associated cardiovascular complications through its specific role in AT. However, underlying mechanisms remain unclear. This study aims to elucidate whether MR regulates mitochondrial function in obesity, resulting in AT premature aging and vascular dysfunction. Obese (db/db) and lean (db/+) mice were treated with an MR antagonist or a specific mitochondria-targeted antioxidant. Mitochondrial and vascular functions were determined by respirometry and myography, respectively. Molecular mechanisms were probed by Western immunoblotting and real-time polymerase chain reaction in visceral AT and arteries and focused on senescence markers and redox-sensitive pathways. db/db mice displayed AT senescence with activation of the p53-p21 pathway and decreased SIRT (sirtuin) levels, as well as mitochondrial dysfunction. Furthermore, the beneficial anticontractile effects of perivascular AT were lost in db/db via ROCK (Rho kinase) activation. MR blockade prevented these effects. Thus, MR activation in obesity induces mitochondrial dysfunction and AT senescence and dysfunction, which consequently increases vascular contractility. In conclusion, our study identifies novel mechanistic insights involving MR, adipose mitochondria, and vascular function that may be of importance to develop new therapeutic strategies to limit obesity-associated cardiovascular complications.Therapeutic Suppression of mTOR (Mammalian Target of Rapamycin) Signaling Prevents and Reverses Salt-Induced Hypertension and Kidney Injury in Dahl Salt-Sensitive Rats9AbstractmTOR (mammalian target of rapamycin) signaling has emerged as a key regulator in a wide range of cellular processes ranging from cell proliferation, immune responses, and electrolyte homeostasis. mTOR consists of 2 distinct protein complexes, mTORC1 (mTOR complex 1) and mTORC2 (mTOR complex 2) with distinct downstream signaling events. mTORC1 has been implicated in pathological conditions, such as cancer and type 2 diabetes mellitus in humans, and inhibition of this pathway with rapamycin has been shown to attenuate salt-induced hypertension in Dahl salt-sensitive rats. Several studies have found that the mTORC2 pathway is involved in the regulation of renal tubular sodium and potassium transport, but its role in hypertension has remained largely unexplored. In the present study, we, therefore, determined the effect of mTORC2 inhibition with compound PP242 on salt-induced hypertension and renal injury in salt-sensitive rats. We found that PP242 not only completely prevented but also reversed salt-induced hypertension and kidney injury in salt-sensitive rats. PP242 exhibited potent natriuretic actions, and chronic administration tended to produce a negative Na(+) balance even during high-salt feeding. The results indicate that mTORC2 and the related downstream associated pathways play an important role in regulation of sodium balance and arterial pressure regulation in salt-sensitive rats. Therapeutic suppression of the mTORC2 pathway represents a novel pathway for the potential treatment of hypertension.Endothelin Receptor Antagonism Improves Lipid Profiles and Lowers PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) in Patients With Chronic Kidney Disease10AbstractDyslipidemia is common in chronic kidney disease (CKD). Despite statins, many patients fail to adequately lower lipids and remain at increased risk of cardiovascular disease. Selective ETA (endothelin-A) receptor antagonists reduce cardiovascular disease risk factors. Preclinical data suggest that ETA antagonism has beneficial effects on circulating lipids. We assessed the effects of selective ETA antagonism on circulating lipids and PCSK9 (proprotein convertase subtilisin/kexin type 9) in CKD. This was a secondary analysis of a fully randomized, double-blind, 3-phase crossover study. Twenty seven subjects with predialysis CKD on optimal cardio- and renoprotective treatment were randomly assigned to receive 6 weeks dosing with placebo, the selective ETA receptor antagonist, sitaxentan, or long-acting nifedipine. We measured circulating lipids and PCSK9 at baseline and then after 3 and 6 weeks. Baseline lipids and PCSK9 did not differ before each study phase. Whereas placebo and nifedipine had no effect on lipids, 6 weeks of ETA antagonism significantly reduced total (−11±1%) and low-density lipoprotein-associated (−20±3%) cholesterol, lipoprotein (a) (−16±2%) and triglycerides (−20±4%); high-density lipoprotein-associated cholesterol increased (+14±2%), P<0.05 versus baseline for all. Additionally, ETA receptor antagonism, but neither placebo nor nifedipine, reduced circulating PCSK9 (−19±2%; P<0.001 versus baseline; P<0.05 versus nifedipine and placebo). These effects were independent of statin use and changes in blood pressure or proteinuria. Selective ETA antagonism improves lipid profiles in optimally managed patients with CKD, effects that may occur through a reduction in circulating PCSK9. ETA receptor antagonism offers a potentially novel strategy to reduce cardiovascular disease risk in CKD. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00810732.Novel Potent Decameric Peptide of Spirulina Platensis Reduces Blood Pressure Levels Through a PI3K (Phosphoinositide-3-Kinase)/AKT/eNOS (Endothelial NO Synthase)-Dependent Mechanism11AbstractConsidered as a superfood of the future, Spirulina platensis matrix has been extensively used because of its beneficial effect on the management of cardiovascular diseases. However, its nutraceutical properties, bioactive compounds, and molecular mechanisms are unknown. Here, we demonstrate that S platensis matrix processed in vitro by simulated gastrointestinal digestion induces direct endothelial nitric oxide (NO)-mediated vasorelaxation of resistance vessels in mice. To gain insight into the bioactive compounds responsible for this effect, we used a complex multistep peptidomic approach to fractionate the crude digest: of the 5 peptide fractions identified (A-E), only fraction E evoked vasorelaxation. High-resolution mass spectrometry-based screening revealed in E the presence of 4 main peptides (SP3-SP6 [spirulina peptides]), of which only SP6 (GIVAGDVTPI) exerted direct endothelium-dependent vasodilation of ex vivo vessels, an effect occurring via a PI3K (phosphoinositide-3-kinase)/AKT (serine/threonine kinase Akt) pathway converging on NO release. In vivo, administration of SP6 evoked a significant hemodynamic effect, reducing blood pressure, an action absent in eNOS (endothelial NO synthase)-deficient mice. Of note, although lower doses of SP6 had no hemodynamic effects, it still enhanced endothelial NO vasorelaxation. Finally, in an experimental model of arterial hypertension, SP6 exerted an antihypertensive effect, improving endothelial vasorelaxation associated with enhanced serum nitrite levels. Based on our results, this novel decameric peptide may extend the possible fields of application for spirulina-derived peptides and could be developed into a promising nonpharmacological approach for the containment of pathologies associated with vascular NO misregulation.Cocaine Exposure Increases Blood Pressure and Aortic Stiffness via the miR-30c-5p-Malic Enzyme 1-Reactive Oxygen Species Pathway12AbstractCocaine abuse increases the risk of cardiovascular mortality and morbidity; however, the underlying molecular mechanisms remain elusive. By using a mouse model for cocaine abuse/use, we found that repeated cocaine injection led to increased blood pressure and aortic stiffness in mice associated with elevated levels of reactive oxygen species (ROS) in the aortas, a phenomenon similar to that observed in hypertensive humans. This ROS elevation was correlated with downregulation of Me1 (malic enzyme 1), an important redox molecule that counteracts ROS generation, and upregulation of microRNA (miR)-30c-5p that targets Me1 expression by directly binding to its 3’UTR (untranslated region). Remarkably, lentivirus-mediated overexpression of miR-30c-5p in aortic smooth muscle cells recapitulated the effect of cocaine on Me1 suppression, which in turn led to ROS elevation. Moreover, in vivo silencing of miR-30c-5p in smooth muscle cells resulted in Me1 upregulation, ROS reduction, and significantly suppressed cocaine-induced increases in blood pressure and aortic stiffness-a similar effect to that produced by treatment with the antioxidant N-acetyl cysteine. Discovery of this novel cocaine—upward arrow miR-30c-5p—downward arrow Me1—upward arrow ROS pathway provides a potential new therapeutic avenue for treatment of cocaine abuse-related cardiovascular disease.Growth Differentiation Factor 11 Promotes Abnormal Proliferation and Angiogenesis of Pulmonary Artery Endothelial Cells13AbstractDisordered proliferation and angiogenesis of pulmonary artery endothelial cells is an important stage in the development of pulmonary arterial hypertension. Recent studies revealed that GDF11 (growth differentiation factor 11) induces endothelial cells proliferation and migration; however, whether GDF11 is directly involved in the pathogenesis of pulmonary arterial hypertension remains unknown. Here, we found that GDF11 was significantly upregulated and activated in 2 experimental pulmonary arterial hypertension models and cultured pulmonary artery endothelial cells. Genetic ablation of gdf11 in endothelial cells rescued pulmonary arterial hypertension features, as demonstrated by right ventricle hypertrophy, right ventricular systolic pressure, hemodynamics, cardiac function, and vascular remodeling. Moreover, we found that hypoxia significantly increased cell cycle progression, proliferation, migration, adhesion, and tube formation, which were significantly inhibited by GDF11 small interfering RNA. These events could be reproduced using cultured pulmonary artery endothelial cells and were dependent on Smad signaling. Moreover, hypoxia-induced GDF11 expression was regulated by the transcription factor zinc finger protein 740, which assisted RNA polymerase in recognizing and binding to the GDF11 promoter sequence located at a site (-753/-744; CCCCCCCCAC) upstream of the gene. This study identified a novel growth and differentiation factor signaling pathway involved in the zinc finger protein 740/GDF11/transforming growth factor-β receptor I/Smad signaling axis and involved in pulmonary artery endothelial cells proliferation and angiogenesis. These results provide critical insights for the development of novel therapeutic strategies for pulmonary arterial hypertension involving components of the GDF11 signaling system.Novel Role for the Immunoproteasome Subunit PSMB10 in Angiotensin II-Induced Atrial Fibrillation in Mice14AbstractAng II (angiotensin II) and inflammation are associated with pathogenesis of atrial fibrillation (AF), but the underlying molecular mechanisms of these events remain unknown. The immunoproteasome has emerged as a critical regulator of inflammatory responses. Here, we investigated its role in Ang II-induced AF in immunosubunit PSMB10 (also known as beta2i or LMP10) knockout (KO) mice. AF was induced by Ang II infusion (2000 ng/minute per kg). PSMB10 expression and trypsin-like activity were increased in atrial tissues and serum from Ang II-treated mice or serum from patients with AF. Moreover, Ang II-infused wild-type (WT) mice had a higher AF and increased atrial fibrosis, reactive oxygen species production, and inflammation compared with saline-treated WT animals. These effects were attenuated in PSMB10 KO mice but were aggravated in recombinant adeno-associated virus serotype 9-PSMB10-treated mice. Administration of IKKβ-specific inhibitor IMD 0354 reduced Ang II-induced AF, reactive oxygen species production, inflammation, and NF-kB (nuclear factor-kB) activation. Mechanistically, Ang II infusion upregulated PSMB10 expression to promote PTEN (phosphatase and tensin homolog deleted on chromosome ten) degradation and AKT1 activation, which not only activated TGF-β-Smad2/3 signaling leading to cardiac fibrosis but also induced IKKβ activation and ubiquitin-mediated degradation of IkBalpha ultimately resulting in activation of NF-kB target genes (IL [interleukin]-1β, IL-6, NOX [NADPH oxidase] 2, NOX4, and CX43 [connexin 43]). Overall, our study identifies immunosubunit PSMB10 as a novel regulator that contributes to Ang II-induced AF and suggests that inhibition of PSMB10 may represent a potential therapeutic target for treating hypertensive AF.Cyclooxygenase-2 Selectively Controls Renal Blood Flow Through a Novel PPARbeta/delta (Peroxisome Proliferator-Activated Receptor-beta/delta)-Dependent Vasodilator Pathway15AbstractCyclooxygenase-2 (COX-2) is an inducible enzyme expressed in inflammation and cancer targeted by NSAIDS. COX-2 is also expressed constitutively in discreet locations where its inhibition drives gastrointestinal and cardiovascular/renal side effects. Constitutive