Abstract 13798: Ablation of the Hypertension Candidate Gene ATP2B1 Results in Increased Blood Pressure and Cardiac Hypertrophic Remodeling

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Sally K Hammad ◽  
Min Zi ◽  
Sukhpal Prehar ◽  
Robert Little ◽  
Ludwig Neyses ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cardiac Hypertrophy ◽  
Diastolic Pressure ◽  
Association Studies ◽  
Weight Ratio ◽  
Blood Pressure Regulation ◽  
Heart Weight ◽  
Genome Wide Association Studies ◽  
Pressure Regulation ◽  
The Impact

Introduction: Hypertension is a major risk factor for cardiac hypertrophy and heart failure. Genome wide association studies have recently identified single nucleotide polymorphisms in ATP2B1 , the gene encoding the calcium extrusion pump, plasma membrane calcium ATPase (PMCA1), as having a strong association with hypertension risk. Hypothesis: PMCA1 plays an important role in regulation of blood pressure and protection against hypertension and cardiac hypertrophy. Aims: We aim to examine whether there is a functional link between PMCA1 and blood pressure regulation, and the development of hypertension. And to determine the impact this link may have on cardiac structure and function. Methods and Results: To study the role of PMCA1 we generated a global PMCA1 heterozygous knockout mouse (PMCA1 Ht ). PMCA1 Ht mice had 46% to 52% reduction in PMCA1 protein expression compared to the WT, in aorta, heart, kidney and brain. To study the mice under hypertensive stress conditions, 3 month old PMCA1 Ht and wild type (WT) mice were infused via minipump with angiotensin II (1mg/Kg/daily) or water as a control. Upon angiotensin treatment, PMCA1 Ht mice showed a significantly greater increase in systolic (62.24±3.05 mmHg) and diastolic pressure (52.68±4.67 mmHg), in comparison to the WT (33.37±2.91 mmHg and 23.94±4.56 mmHg, respectively), P<0.001, n=12. Moreover, PMCA1 Ht mice showed a significantly greater hypertrophic response as indicated by a greater heart weight to tibia length ratio, cardiomyocyte cell size (410±18.7 μm 2 ), compared to WT mice (340.4±9.8 μm 2 ), and increased expression of B-type natriuretic peptide (BNP), 2.36 ± 0.25 fold change, n =5-6, P< 0.01. Echocardiography showed no significant changes between PMCA1 Ht and WT mice, in heart rate, and in cardiac function, as indicated by fractional shortening and ejection fraction. In addition, PMCA1 Ht mice showed no sign of lung congestion as indicated by lung weight to body weight ratio. Conclusion: ATP2B1 deletion leads to increased blood pressure and cardiac hypertrophy. This provides functional evidence that PMCA1 is involved in blood pressure regulation and protects against the development of hypertension and cardiac hypertrophy.

scholarly journals Genetic mechanisms of human hypertension and their implications for blood pressure physiology

2017 ◽  
Vol 49 (11) ◽  
pp. 630-652 ◽  
Author(s):  
Eric Seidel ◽  
Ute I. Scholl
Keyword(s):  
Blood Pressure ◽  
Large Scale ◽  
Association Studies ◽  
Blood Pressure Regulation ◽  
Genome Wide Association Studies ◽  
Pressure Regulation ◽  
Public Health Burden ◽  
Sequencing Studies ◽  
Hereditary Factors ◽  
Genetic Mechanisms

Hypertension, or elevated blood pressure, constitutes a major public health burden that affects more than 1 billion people worldwide and contributes to ~9 million deaths annually. Hereditary factors are thought to contribute to up to 50% of interindividual blood pressure variability. Blood pressure in the general population approximately shows a normal distribution and is thought to be a polygenic trait. In rare cases, early-onset hypertension or hypotension are inherited as Mendelian traits. The identification of the underlying Mendelian genes and variants has contributed to our understanding of the physiology of blood pressure regulation, emphasizing renal salt handling and the renin angiotensin aldosterone system as players in the determination of blood pressure. Genome-wide association studies (GWAS) have revealed more than 100 variants that are associated with blood pressure, typically with small effect sizes, which cumulatively explain ~3.5% of blood pressure trait variability. Several GWAS associations point to a role of the vasculature in the pathogenesis of hypertension. Despite these advances, the majority of the genetic contributors to blood pressure regulation are currently unknown; whether large-scale exome or genome sequencing studies will unravel these factors remains to be determined.

The impact of polymorphisms in the gene encoding aldosterone synthase (CYP11B2) on steroid synthesis and blood pressure regulation

2004 ◽  
Vol 217 (1-2) ◽  
pp. 243-247 ◽  
Author(s):  
John M.C Connell ◽  
Robert Fraser ◽  
Scott M MacKenzie ◽  
Elaine C Friel ◽  
Mary C Ingram ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Blood Pressure Regulation ◽  
Pressure Regulation ◽  
Gene Encoding ◽  
Steroid Synthesis ◽  
Aldosterone Synthase ◽  
The Impact

scholarly journals The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals

2016 ◽  
Vol 48 (10) ◽  
pp. 1171-1184 ◽  
Author(s):  
Georg B Ehret ◽  
◽  
Teresa Ferreira ◽  
Daniel I Chasman ◽  
Anne U Jackson ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Association Studies ◽  
Blood Pressure Regulation ◽  
Pressure Regulation ◽  
Target Organs

scholarly journals Cardioprotective Effects of the Novel Compound Vastiras in a Preclinical Model of End-Organ Damage

Hypertension ◽  
2020 ◽  
Vol 75 (5) ◽  
pp. 1195-1204
Author(s):  
Raffaele Altara ◽  
Gustavo J.J. da Silva ◽  
Michael Frisk ◽  
Francesco Spelta ◽  
Fouad A. Zouein ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cardiac Hypertrophy ◽  
Natriuretic Peptide ◽  
Renal Damage ◽  
Weight Ratio ◽  
Hypertensive Heart Disease ◽  
Heart Weight ◽  
Preclinical Model ◽  
Continuous Administration ◽  
Positive Effects

Cardiac hypertrophy and renal damage associated with hypertension are independent predictors of morbidity and mortality. In a model of hypertensive heart disease and renal damage, we tested the actions of continuous administration of Vastiras, a novel compound derived from the linear fragment of ANP (atrial natriuretic peptide), namely pro-ANP 31–67 , on blood pressure and associated renal and cardiac function and remodeling. Of note, this peptide, unlike the ring structured forms, does not bind to the classic natriuretic peptide receptors. Dahl/Salt–Sensitive rats fed a 4% NaCl diet for 6 weeks developed hypertension, cardiac hypertrophy, and renal damage. Four weeks of treatment with 50 to 100 ng/kg per day of Vastiras exhibited positive effects on renal function, independent of blood pressure regulation. Treated rats had increased urine excretion, natriuresis, and enhanced glomerular filtration rate. Importantly, these favorable renal effects were accompanied by improved cardiac structure and function, including attenuated cardiac hypertrophy, as indicated by decreased heart weight to body weight ratio, relative wall thickness, and left atrial diameter, as well as reduced fibrosis and normalized ratio of the diastolic mitral inflow E wave to A wave. A renal subtherapeutic dose of Vastiras (25 ng/kg per day) induced similar protective effects on the heart. At the cellular level, cardiomyocyte size and t-tubule density were preserved in Vastiras-treated compared with untreated animals. In conclusion, these data demonstrate the cardiorenal protective actions of chronic supplementation of a first-in-class compound, Vastiras, in a preclinical model of maladaptive cardiac hypertrophy and renal damage induced by hypertension.

Hypertension and Cardiac Hypertrophy in Growth Hormone-Deficient Rats

1994 ◽  
Vol 87 (2) ◽  
pp. 239-243 ◽  
Author(s):  
Stephen B. Harrap ◽  
Shari R. Datodi ◽  
Emma K. Crapper ◽  
Leon A. Bach
Keyword(s):  
Blood Pressure ◽  
Growth Hormone ◽  
Body Weight ◽  
Cardiac Hypertrophy ◽  
Weight Ratio ◽  
The Body ◽  
Hormone Deficiency ◽  
Heart Weight ◽  
Deoxycorticosterone Acetate ◽  
F344 Rats

1. Growth hormone may influence cardiac growth during post-natal maturation or in response to hypertension, and the growth-hormone deficient dwarf rat model offers an opportunity to study this question. 2. We compared the blood pressure and heart weight of dwarf rats and Fischer (F344) control rats in early adulthood, after two hypertensive stimuli: unilateral renal ischaemia (two-kidney, one-clip) or the administration of deoxycorticosterone acetate and saline drinking fluid. 3. In untreated animals at 13 weeks of age the body weight of dwarf rats was significantly less than that of F344 rats, but the mean arterial pressure was similar. Although the hearts of dwarf rats were smaller than those of F344 rats, the heart weight/body weight ratio was significantly greater in dwarf rats. 4. Both dwarf and F344 rats developed similar hypertensive mean arterial pressures 5 weeks after left renal artery clipping or treatment with deoxycorticosterone acetate salt. The heart weights of hypertensive dwarf and F344 rats were equivalent, indicating a proportionally greater increase in cardiac size in dwarf rats for the same rise in blood pressure. 5. The plasma insulin-like growth factor-I level was markedly lower in dwarf than in F344 rats, and hypertension did not have any significant effects on these levels. 6. These findings indicate that the developmental increase in blood pressure and heart size in growing animals and the adaptive cardiac hypertrophy accompanying hypertension are not affected by growth hormone deficiency.

Abstract MP166: PRKAR1A Deficiency Abrogates Cardiac Hypertrophy Through Inhibition of Mitochondrial Fission

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Yuening Liu ◽  
Peng Xia ◽  
Jingrui Chen ◽  
Patricia W Bandettini ◽  
Lawrence S Kirschner ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Postnatal Development ◽  
Contractile Function ◽  
Mitochondrial Fission ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
Cardiac Complications ◽  
The Impact

Protein kinase A (PKA) is pivotal for cardiac function of human heart, and its dysregulation is involved with various cardiac pathologies. PKA regulatory subunit 1α (R1α, encoded by PRKAR1A gene) controls PKA kinase activity by sequestering the PKA catalytic subunits. Patients with PRKAR1A mutations are often diagnosed with Carney complex (CNC) and may die prematurely from cardiac complications such as heart failure. However, it remains unknown whether PRKAR1A deficiency interferes with normal heart growth during postnatal development. Here, we show that left ventricular mass is reduced in young CNC patients with PRKAR1A mutations or deletions. To investigate the impact of PRKAR1A deficiency on heart growth, we generated cardiac-specific PRKAR1A heterozygous knockout mice. Ablation of the PRKAR1A gene in mice increased cardiac PKA activity, reduced heart weight to body weight ratio and cardiomyocyte size without altering contractile function. Cardiomyocyte hypertrophy in response to activation of the α1-adrenergic receptor, was completely abolished by silencing of PRKAR1A . Mechanistically, depletion of PRKAR1A provoked PKA-dependent phosphorylation of the mitochondrial fission protein Drp1 at S637, resulting in impaired mitochondrial fission and diminished cardiomyocyte hypertrophy. In conclusion, PRKAR1A deficiency abrogates cardiac hypertrophy during postnatal development, likely through inhibiting Drp1-mediated mitochondrial fission. Our study provides novel mechanistic insights regarding the cardiac mortality associated with CNC.

Impact of in vitro embryo culture and transfer on blood pressure regulation in the adolescent lamb

2020 ◽  
pp. 1-7
Author(s):  
Monalisa Padhee ◽  
I. Caroline McMillen ◽  
Song Zhang ◽  
Severence M. MacLaughlin ◽  
James A. Armitage ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Renal Artery ◽  
Mrna Expression ◽  
Embryo Culture ◽  
Blood Pressure Regulation ◽  
Pressure Regulation ◽  
Basal Blood Pressure ◽  
Periconceptional Period ◽  
The Impact

Abstract Nutrition during the periconceptional period influences postnatal cardiovascular health. We determined whether in vitro embryo culture and transfer, which are manipulations of the nutritional environment during the periconceptional period, dysregulate postnatal blood pressure and blood pressure regulatory mechanisms. Embryos were either transferred to an intermediate recipient ewe (ET) or cultured in vitro in the absence (IVC) or presence of human serum (IVCHS) and a methyl donor (IVCHS+M) for 6 days. Basal blood pressure was recorded at 19–20 weeks after birth. Mean arterial pressure (MAP) and heart rate (HR) were measured before and after varying doses of phenylephrine (PE). mRNA expression of signaling molecules involved in blood pressure regulation was measured in the renal artery. Basal MAP did not differ between groups. Baroreflex sensitivity, set point, and upper plateau were also maintained in all groups after PE stimulation. Adrenergic receptors alpha-1A (αAR1A), alpha-1B (αAR1B), and angiotensin II receptor type 1 (AT1R) mRNA expression were not different from controls in the renal artery. These results suggest there is no programmed effect of ET or IVC on basal blood pressure or the baroreflex control mechanisms in adolescence, but future studies are required to determine the impact of ET and IVC on these mechanisms later in the life course when developmental programming effects may be unmasked by age.

Inhibition of NF-κB induces regression of cardiac hypertrophy, independent of blood pressure control, in spontaneously hypertensive rats

2005 ◽  
Vol 289 (1) ◽  
pp. H20-H29 ◽  
Author(s):  
Sudhiranjan Gupta ◽  
David Young ◽  
Subha Sen
Keyword(s):  
Blood Pressure ◽  
Cardiac Hypertrophy ◽  
Spontaneously Hypertensive Rats ◽  
Weight Ratio ◽  
Cardiac Mass ◽  
Heart Weight ◽  
Pyrrolidine Dithiocarbamate ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Iκb Kinase

The transcription factor nuclear factor (NF)-κB plays a leading role in cardiac hypertrophy associated with heart failure, but whether it is involved in cardiac mass reduction is not known. We evaluated whether inhibiting the NF-κB cascade with pyrrolidine dithiocarbamate (PDTC) in spontaneously hypertensive rats (SHRs) and age-matched Wistar-Kyoto rats (WKYs) affected hypertrophy. We measured NF-κB signaling components [NF-κB translocation, IκBα, p65, mRNA and protein levels, and IκB kinase-β (IKKβ) activity] at 12 and 36 wk in WKYs and SHRs and at 10 wk in PDTC-treated rats ( n = 9). NF-κB activation was also evaluated in rats treated for 10 wk with captopril or hydralazine alone or with either drug plus PDTC. All components were increased in SHRs compared with WKYs. After PDTC treatment, NF-κB activity was inhibited, and heart weight-to-body weight ratio in SHRs was significantly attenuated (3.52 ± 0.04 to 3.32 ± 0.05 mg/kg). Captopril treatment significantly reduced cardiac mass (3.5 vs. 3.05 mg/kg; n = 9) and inhibited NF-κB activity (169.71 ± 5.70 to 106.7 ± 12.44). Hydralazine had no effect on cardiac mass (3.5 vs. 3.42 mg/kg) or NF-κB activity (169.71 ± 5.70 to 155.52 ± 6.11). Hydralazine plus PDTC reduced blood pressure (191.16 ± 1.7 to 158.5 ± 2.36 mmHg) and inhibited NF-κB activity (169.71 ± 5.70 to 97.29 ± 3.65). Our data suggest that 1) cardiac hypertrophy in SHRs is partly due to NF-κB activation, 2) inhibition of NF-κB activity by PDTC parallels regression of hypertrophy, and 3) regression of hypertrophy is partly due to inhibition of NF-κB activity, independent of hypertension. The relationship between NF-κB activity and cardiac remodeling is causal, not coincidental.

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