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Intrauterine Growth Restriction Programs Intergenerational Transmission of Pulmonary Arterial Hypertension and Endothelial Dysfunction via Sperm Epigenetic Modifications

期刊: HYPERTENSION, 2019; 74 (5)

Intrauterine life represents a window of phenotypic plasticity which carries consequences for later health in adulthood as well as health of subsequent generations. Intrauterine growth-restricted fetuses (intrauterine growth restriction [IUGR]) have a higher risk of pulmonary arterial hypertension in adulthood. Endothelial dysfunction, characterized by hyperproliferation, invasive migration, and disordered angiogenesis, is a hallmark of pulmonary arterial hypertension pathogenesis. Growing evidence suggests that intergenerational transmission of disease, including metabolic syndrome, can be induced by IUGR. Epigenetic modification of the paternal germline is implicated in this transmission. However, it is unclear whether offspring of individuals born with IUGR are also at risk of developing pulmonary arterial hypertension and endothelial dysfunction. Using a model of maternal caloric restriction to induce IUGR, we found that first and second generations of IUGR exhibited elevated pulmonary arterial pressure, myocardial, and vascular remodeling after prolonged exposure to hypoxia. Primary pulmonary vascular endothelial cells (PVECs) from both first and second generations of IUGR exhibited greater proliferation, migration, and angiogenesis. Moreover, in 2 generations, PVECs-derived ET-1 (endothelin-1) was activated by IUGR and hypoxia, and its knockdown mitigated PVECs dysregulation. Most interestingly, within ET-1 first intron, reduced DNA methylation and enhanced tri-methylation of lysine 4 on histone H3 were observed in PVECs and sperm of first generation of IUGR, with DNA demethylation in PVECs of second generation of IUGR. These results suggest that IUGR permanently altered epigenetic signatures of ET-1 from the sperm and PVECs in the first generation, which was subsequently transferred to PVECs of offspring. This mechanism would yield 2 generations with endothelial dysfunction and pulmonary arterial hypertension-like pathophysiological features in adulthood.

IF:7.02

NaHCO3 Dilates Mouse Afferent Arteriole Via Na+/HCO3- Cotransporters NBCs

期刊: HYPERTENSION, 2019; 74 (5)

Sodium bicarbonate has long been used to treat chronic kidney disease. It has been demonstrated to slow the decline in glomerular filtration rate in chronic kidney disease patient; however, the mechanisms are not completely understood. We hypothesized that NaHCO3 dilates afferent arterioles (Af-Art) by stimulating nitric oxide (NO) release mediated by the Na+/HCO3- cotransporter (NBC) contributing to the elevation in glomerular filtration rate. Isolated microperfused mouse renal Af-Art, preconstricted with norepinephrine (1 mu mol/L), dilated 45 +/- 2% (n=6, P<0.05) in response to NaHCO3 (44 mmol/L). Whereas, NaCl solution containing the same Na+ concentration was not effective. The mRNA for NBCn1 and NBCe1 were detected in microdissected Af-Art using reverse transcription-polymerase chain reaction and quantitative polymerase chain reaction. The Af-Art intracellular pH measured with 2 ',7 '-bis-(2-carboxyethyl)-5-(and-6) carboxyfluorescein, acetoxymethyl ester increased significantly by 0.29 +/- 0.02 (n=6; P<0.05) in the presence of NaHCO3, which was blunted by N-cyanosulphonamide compound (S0859) that is an inhibitor of the NBC family. After clamping the intracellular pH with 10 mu M nigericin, changing the bath solution pH from 7.4 to 7.8 still dilates the Af-Art by 53 +/- 4% (n=7; P<0.005) and increases NO generation by 22 +/- 3% (n=7; P<0.005). Both pH-induced NO generation and vasodilation were blocked by L-NG-Nitroarginine Methyl Ester. NaHCO3 increased NO generation in Af-Art by 19 +/- 4% (n=5; P<0.005) and elevated glomerular filtration rate in conscious mice by 36% (233 versus 318 ul/min; n=9-10; P<0.0001). S0859 and L-NG-nitroarginine methyl ester blocked NaHCO3-induced increases in NO generation and vasodilation. We conclude that NBCn1 and NBCe1 are expressed in Af-Art and that NaHCO3 dilates Af-Art via NBCs mediated by NO that increases the glomerular filtration rate.

IF:7.02

Long-Term Burden of Higher Body Mass Index and Adult Arterial Stiffness Are Linked Predominantly Through Elevated Blood Pressure

期刊: HYPERTENSION, 2019; 73 (1)

Obesity and hypertension are important risk factors of arterial stiffness. However, the complex relationship between increased body mass index (BMI), elevated blood pressure (BP), and arterial stiffness is largely unknown. We aim to examine the mediation effect of elevated BP on the association of early life BMI, long-term burden, and trend of BMI with arterial stiffness in midlife. The longitudinal study cohort consisted of 1190 participants (829 whites and 361 blacks, 518 males, mean age=40.0 years at follow-up) who had been examined for BMI and BP 4 to 15 times from childhood and aortic-femoral pulse wave velocity (afPWV) in adulthood, with a mean follow-up period of 30.3 years. Total area under the curve (AUC(t)) and incremental AUC (AUC(i)) were calculated in random-effects models and used as long-term measures of BMI and BP. Total effects of BMI measures on adult afPWV, adjusted for covariates were all significant without adult BMI and systolic BP (SBP) measures included in the models. The mediation effects of adult SBP (20.2%) and SBP AUC(i) (16.9%) were significant on the childhood BMI-afPWV association. Adult SBP showed significant mediation effects of 36.7% on the BMI AUC(i)-afPWV association and 36.4% on the BMI AUC(t)-afPWV association. The mediation effect of SBP AUC(i) was estimated at 63.3% (P<0.01) on the BMI AUC(i)-afPWV association. Diastolic BP had similar total and mediation effects. These findings suggest that the association of increased childhood BMI and its cumulative burden with adult arterial stiffness measured as afPWV is predominantly mediated through the long-term and increasing trend of BP.

IF:7.02

Norepinephrine-Induced Stimulation of Kir4.1/Kir5.1 Is Required for the Activation of NaCl Transporter in Distal Convoluted Tubule

期刊: HYPERTENSION, 2019; 73 (1)

The stimulation of -adrenergic receptor increases thiazide-sensitive NaCl cotransporter (NCC), an effect contributing to salt-sensitive hypertension by sympathetic stimulation. We now test whether the stimulation of -adrenergic receptor-induced activation of NCC is achieved through activating basolateral Kir4.1 in the distal convoluted tubule (DCT). Application of norepinephrine increased the basolateral 40 pS K+ channel (Kir4.1/Kir5.1 heterotetramer) in the DCT. The stimulatory effect of norepinephrine on the K+ channel was mimicked by cAMP analogue but abolished by inhibiting PKA (protein kinase A). Also, the effect of norepinephrine on the K+ channel in the DCT was recapitulated by isoproterenol but not by -adrenergic agonist and blocked by propranolol, suggesting that norepinephrine effect on the K+ channel was mediated by -adrenergic receptor. The whole-cell recording shows that norepinephrine and isoproterenol increased DCT K+ currents and shifted the K+ current (I-K) reversal potential to negative range (hyperpolarization). Continuous norepinephrine perfusion (7 days) increased DCT K+ currents, hyperpolarized I-K reversal potential, and increased the expression of total NCC/phosphorylated NCC, but it had no significant effect on the expression of NKCC2 (type 2 Na-Cl-K cotransporter) and ENaC- (epithelial Na channel- subunit). Renal clearance study demonstrated that norepinephrine perfusion augmented thiazide-induced urinary Na+ excretion only in wild-type but not in kidney-specific Kir4.1 knockout mice, suggesting that Kir4.1 is required for mediating the effect of norepinephrine on NCC. However, norepinephrine perfusion did not affect urinary K+ excretion. We conclude that the stimulation of -adrenergic receptor activates the basolateral Kir4.1 in the DCT and that the activation of Kir4.1 is required for norepinephrine-induced stimulation of NCC.

IF:7.02

Immunoproteasome Subunit 5i Promotes Ang II (Angiotensin II)-Induced Atrial Fibrillation by Targeting ATRAP (Ang II Type I Receptor-Associated Protein) Degradation in Mice

期刊: HYPERTENSION, 2019; 73 (1)

Atrial fibrillation (AF) is the most common type of cardiac arrhythmia and increases the risk of stroke, heart failure, and death. Ang II (angiotensin II) triggers AF, mainly through stimulation of the AT1R (Ang II type I receptor). The immunoproteasome is a highly efficient proteolytic machine derived from the constitutive proteasome, but the role it plays in regulating AT1R activation and triggering AF remains unknown. Here, we show that among the catalytic subunits, 5i (PSMB8) expression, and chymotrypsin-like activity were the most significantly upregulated in atrial tissue of Ang II-infused mice or serum from patients with AF. 5i KO (5i knockout) in mice markedly attenuated Ang II-induced AF incidence, atrial fibrosis, inflammatory response, and oxidative stress compared with WT (wild type) animals, but injection with recombinant adeno-associated virus serotype 9-5i increased these effects. Moreover, we found that ATRAP (AT1R-associated protein) was a target of 5i. Overexpression of ATRAP significantly attenuated Ang II-induced atrial remodeling and AF in recombinant adeno-associated virus serotype 9-5i-injected mice. Mechanistically, Ang II upregulated 5i expression to promote ATRAP degradation, which resulted in activation of AT1R-mediated NF-B signaling, increased NADPH oxidase activity, increased TGF (transforming growth factor)-1/Smad signaling, and altered the expression of Kir2.1 and CX43 (connexin 43) in the atria, thereby affecting atrial remodeling and AF. In summary, this study identifies 5i as a negative regulator of ATRAP stability that contributes to AT1R activation and to AF, highlighting that targeting 5i activity may represent a potential therapeutic approach for the treatment of hypertensive AF.

IF:7.02

Role of Corin in Blood Pressure Regulation in Normotensive and Hypertensive Pregnancy: A Prospective Study

期刊: HYPERTENSION, 2019; 73 (2)

Corin (an atrial natriuretic peptide-converting enzyme) represents a potential biomarker for gestational hypertensive disorders; yet, its role in blood pressure (BP) regulation throughout pregnancy remains unclear. We investigated the time course of change in blood corin content in relation to BP and sympathetic nerve activity throughout pregnancy. Forty-four women (29 +/- 0.9 years) participated. Following-term, 23 had low-risk (no personal history of gestational hypertensive disorders) normal pregnancies, 13 had high-risk (personal history of gestational hypertensive disorders) normal pregnancies, and 8 developed gestational hypertension. BP, heart rate, muscle sympathetic nerve activity, and serum corin were measured before pregnancy, during early (4-8 weeks) and late pregnancy (32-36 weeks), and postpartum (6-10 weeks). Overall, compared with prepregnancy, corin remained unchanged during early pregnancy, increased markedly during late pregnancy (P<0.001), and returned to prepregnancy levels postpartum. In women who developed gestational hypertension, the change in corin from early to late pregnancy was greater than those with low-risk normal pregnancies (971 +/- 134 versus 486 +/- 79 pg/mL; P<0.05). Throughout pregnancy, BP and muscle sympathetic nerve activity were augmented in women with gestational hypertension (all P<0.05). Finally, changes in corin from early to late pregnancy were related to all indices of BP (R=0.454-0.551; all P<0.01) in late pregnancy, whereas burst frequency, burst incidence, and total muscle sympathetic nerve activity (R=0.576-0.614; all P<0.001) in early pregnancy were related to changes in corin from early to late pregnancy. Corin plays a unique role in BP regulation throughout normotensive and, especially, hypertensive pregnancy and may represent a promising biomarker for determining women at high risk of adverse pregnancy outcome.

IF:7.02

GRP78 (Glucose-Regulated Protein of 78 kDa) Promotes Cardiomyocyte Growth Through Activation of GATA4 (GATA-Binding Protein 4)

期刊: HYPERTENSION, 2019; 73 (2)

The heart manifests hypertrophic growth in response to elevation of afterload pressure. Cardiac myocyte growth involves new protein synthesis and membrane expansion, of which a number of cellular quality control machineries are stimulated to maintain function and homeostasis. The unfolded protein response is potently induced during cardiac hypertrophy to enhance protein-folding capacity and eliminate terminally misfolded proteins. However, whether the unfolded protein response directly regulates cardiac myocyte growth remains to be fully determined. Here, we show that GRP78 (glucose-regulated protein of 78 kDa)an endoplasmic reticulum-resident chaperone and a critical unfolded protein response regulatoris induced by cardiac hypertrophy. Importantly, overexpression of GRP78 in cardiomyocytes is sufficient to potentiate hypertrophic stimulus-triggered growth. At the in vivo level, TG (transgenic) hearts overexpressing GRP78 mount elevated hypertrophic growth in response to pressure overload. We went further to show that GRP78 increases GATA4 (GATA-binding protein 4) level, which may stimulate Anf (atrial natriuretic factor) expression and promote cardiac hypertrophic growth. Silencing of GATA4 in cultured neonatal rat ventricular myocytes significantly diminishes GRP78-mediated growth response. Our results, therefore, reveal that protein-folding chaperone GRP78 may directly enhance cardiomyocyte growth by stimulating cardiac-specific transcriptional factor GATA4.

IF:7.02

Regulation of Atrial Fibrosis by the Bone

期刊: HYPERTENSION, 2019; 73 (2)

MR (mineralocorticoid receptor) antagonists have been demonstrated to provide beneficial effects on preventing atrial fibrosis. However, the underlying cellular and molecular mechanisms remain unclear. We aim to determine the role of osteoblast MR in atrial fibrosis and to explore the underlying mechanism. Using osteoblast MR knockout mouse in combination with mutant TGF (transforming growth factor)-1 transgenic mouse, we demonstrated that MR deficiency in osteoblasts significantly attenuated atrial fibrosis. Mechanistically, MR directly regulated expression of OCN (osteocalcin) in osteoblasts. Both carboxylated and undercarboxylated OCNs (ucOC) were less secreted in osteoblast MR knockout mice. Mutant TGF-1 transgenic mice supplemented with recombinant ucOC showed aggravated atrial fibrosis. In cultured atrial fibroblasts, ucOC treatment promoted proliferation and migration of atrial fibroblasts, whereas cotreatment with an antagonist for a GPRC6A (G-protein-coupled receptor, family C, group 6, member A) abolished these effects. Western blotting analysis revealed upregulation of PKA (protein kinase A) and CREB (cAMP-response element-binding protein) phosphorylation after ucOC treatment. Inhibition of PKA with its antagonist reduced ucOC-induced proliferation and migration of atrial fibroblasts. Finally, the impact of osteoblast MR deficiency on atrial fibrosis was abolished by ucOC administration in mutant TGF-1 transgenic mice. Taken together, MR deficiency in osteoblasts attenuated atrial fibrosis by downregulation of OCN to promote proliferation and migration of atrial fibroblasts.

IF:7.02

Targeted Delivery of Sildenafil for Inhibiting Pulmonary Vascular Remodeling

期刊: HYPERTENSION, 2019; 73 (3)

Pulmonary arterial hypertension is a fatal lung disease caused by the progressive remodeling of small pulmonary arteries (PAs). Sildenafil can prevent the remodeling of PAs, but conventional sildenafil formulations have shown limited treatment efficacy for their poor accumulation in PAs. Here, glucuronic acid (GlcA)-modified liposomes (GlcA-Lips) were developed to improve the delivery of sildenafil to aberrant over-proliferative PA smooth muscle cells via targeting the GLUT-1 (glucose transport-1), and, therefore, inhibiting the remodeling of PAs in a monocrotaline-induced PA hypertension model. GlcA-Lips encapsulating sildenafil (GlcA-sildenafil-Lips) had a size of 90 nm and a pH-sensitive drug release pattern. Immunostaining assay indicated the overexpression of GLUT-1 in PA smooth muscle cells. Cellular uptake studies showed a 1-fold increase of GlcA-Lips uptake by PA smooth muscle cells and pharmacokinetics and biodistribution experiments indicated longer blood circulation time of GlcA-Lips and increased ability to target PAs by 1-fold after 8 hours administration. Two-week treatment indicated GlcA-sildenafil-Lips significantly inhibited the remodeling of PAs, with a 32% reduction in the PA pressure, a 41% decrease in the medial thickening, and a 44% reduction of the right ventricle cardiomyocyte hypertrophy, and improved survival rate. Immunohistochemical analysis showed enhanced expression of caspase-3, after administration of GlcA-sildenafil-Lips, and reduced expression of P-ERK1/2 (phosphorylated ERK1/2) and HK-2 (hexokinase-2), and increased level of eNOS (endothelial nitric oxide synthase) and cyclic GMP (cGMP). In conclusion, targeted delivery of sildenafil to PA smooth muscle cells with GlcA-Lips could effectively inhibit the remodeling of PAs in the monocrotaline-induced PA hypertension.

IF:7.02

Pregnancy Increases Ca2+ Sparks/Spontaneous Transient Outward Currents and Reduces Uterine Arterial Myogenic Tone

期刊: HYPERTENSION, 2019; 73 (3)

Spontaneous transient outward currents (STOCs) at physiological membrane potentials of vascular smooth muscle cells fundamentally regulate vascular myogenic tone and blood flow in an organ. We hypothesize that heightened STOCs play a key role in uterine vascular adaptation to pregnancy. Uterine arteries were isolated from nonpregnant and near-term pregnant sheep. Ca2+ sparks were measured by confocal microscopy, and STOCs were determined by electrophysiological recording in smooth muscle cells. Percentage of Ca2+ spark firing myocytes increased dramatically at the resting condition in uterine arterial smooth muscle of pregnant animals, as compared with nonpregnant animals. Pregnancy upregulated the expression of RyRs (ryanodine receptors) and significantly boosted Ca2+ spark frequency. Ex vivo treatment of uterine arteries of nonpregnant sheep with estrogen and progesterone imitated pregnancy-induced RyR upregulation. STOCs occurred at much more negative membrane potentials in uterine arterial myocytes of pregnant animals. STOCs in uterine arterial myocytes were diminished by inhibiting large-conductance Ca2+-activated K+ (BKCa) channels and RyRs, thus functionally linking Ca2+ sparks and BKCa channel activity to STOCs. Pregnancy and steroid hormone treatment significantly increased STOCs frequency and amplitude in uterine arteries. Of importance, inhibition of STOCs with RyR inhibitor ryanodine eliminated pregnancy-and steroid hormone-induced attenuation of uterine arterial myogenic tone. Thus, the present study demonstrates a novel role of Ca2+ sparks and STOCs in the regulation of uterine vascular tone and provides new insights into the mechanisms underlying uterine vascular adaptation to pregnancy.

IF:7.02

Aging, Arterial Stiffness, and Blood Pressure Association in Chinese Adults

期刊: HYPERTENSION, 2019; 73 (4)

Arterial stiffness and blood pressure (BP) both increase with aging synchronously. Whether elevated BP results from thickening of arterial wall or vice versa is controversial in previous studies. This study included 17 862 participants without history of myocardial infarction, stroke, atrial fibrillation or flutter, or cancer and with brachial-ankle pulse wave velocity (baPWV) and BP measurements during 2010 to 2016. Age was calculated from the self-reported birthdate to the first date of baPWV examination. Mediation analyses were applied to assess the mediation effect by baPWV in the association between age and BP. Temporal relation between baPWV and BP was assessed by cross-lagged analyses among 1508 participants with repeated assessment of baPWV. We found that systolic BP increased 0.47 (95% CI, 0.45-0.49) mm Hg per 1 year older by the mediation effect of baPWV and that the direct effect of aging on systolic BP was -0.07 (95% CI, -0.09 to -0.05) mm Hg per 1 year older. The standard regression coefficient from baseline baPWV to follow-up systolic BP was 0.09 (95% CI, 0.04-0.15), which was greater than the standard regression coefficient from baseline systolic BP to follow-up baPWV (0.01; 95% CI, -0.04 to 0.06). Arterial stiffness mediated the positive association between aging and BP, and arterial stiffness might precede elevated BP. Clinical Trial Registration-URL: http://www.chictr.org.cn. Unique identifier: ChiCTR-TNRC-11001489.

IF:7.02

Shear-Sensitive lncRNA AF131217.1 Inhibits Inflammation in HUVECs via Regulation of KLF4

期刊: HYPERTENSION, 2019; 73 (5)

Atherosclerosis 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-alpha (tumor necrosis factor-alpha) 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-a. Mechanistic investigations indicated that AF131217.1 acted as a competing endogenous RNA for miR-1283-p, 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.

IF:7.02

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