Hemin and L-arginine regulation of blood pressure in spontaneous hypertensive rats.

Perturbation in heme metabolism is known to affect the level and activity of hemoproteins, including cytochrome P450-dependent arachidonic acid metabolism. The latter has been associated with elevation in blood pressure seen in spontaneously hypertensive rats. The effect of heme arginate and its components, arginine and heme, on cytochrome P450 levels and blood pressure in spontaneously hypertensive rats were studied. Administration of heme arginate or heme alone at doses of 9 to 30 mg/kg body wt/day for 4 days resulted in a marked decrease of blood pressure in spontaneously hypertensive rats, whereas blood pressure in rats receiving the vehicle control was not affected. Similarly, L-arginine, but not D-arginine, in a dose-dependent manner decreased blood pressure in spontaneously hypertensive rats. The maximal change in blood pressure was achieved at 100 mg/kg body wt of arginine and was associated with a significant increase in heme oxygenase activity. A higher concentration (500 mg/kg) did not cause an additional decrease in blood pressure but further increased heme oxygenase activity. The arginine-induced heme oxygenase activity was suppressed by Sn-protoporphyrin. Administration of heme to spontaneously hypertensive rats resulted in an accumulation of heme oxygenase mRNA, which was accompanied by an increase in enzyme activity. The increase in heme oxygenase activity was also prevented by Sn-protoporphyrin. It is postulated that heme treatment resulted in an increase in heme oxygenase mRNA, which consequently led to a diminution of cellular heme and depletion of hemoproteins, such as the cytochrome P450 arachidonate metabolizing enzymes.(ABSTRACT TRUNCATED AT 250 WORDS)

Download Full-text

Abstract 181: Overexpression of Arachidonic Acid Cytochrome P450 Expoxygenases Prevents the Development of High Blood Pressure via Enhancing Atrial Natriuretic Peptide in Spontaneously Hypertensive Rats

Circulation ◽

10.1161/circ.116.suppl_16.ii_14-b ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Dao Wen Wang ◽

Bin Xiao ◽

Yong Wang ◽

Xiaojun Xiong ◽

Darryl C Zeldin

Keyword(s):

Blood Pressure ◽

Cytochrome P450 ◽

Atrial Natriuretic Peptide ◽

Natriuretic Peptide ◽

Spontaneously Hypertensive Rats ◽

Hypotensive Effect ◽

Hypertensive Rats ◽

Spontaneously Hypertensive ◽

Atrial Natriuretic

Cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) have potent vasodilatory and diuretic feature, and therefore potentially hypotensive effect. No in vivo studies, however, were performed to support it. This study investigated the hypothesis via overexpressing CYP epoxygense genes in spontaneously hypertensive rats (SHR). Recombinant adeno-associated virus vector (rAAV) was utilized to mediate long-term transfection of CYP2J2 and CYP2C11 genes, respectively, in adult SHR, and animal systolic blood pressure (SBP) was monitored using arterial caudilis indirect manometric method. Results showed that at 2 months the urinary excretion of stable hydrolysis metabolic product of 14, 15-EE, 14–15-DHET increased by 11 and 8.7 folds in rAAV-2J2 and rAAV-2C11 groups, respectively, compared with AAV-GFP-treated rats. (2) SBP in 2J2- and 2C11-treated rats decreased from 175.0 ± 2.8mHg to 163.5 ± 5.8mmHg and 161.2 ± 6.1 mmHg, respectively, ( p <0.01) at month 2, and it is 165.0 ± 4.7 mmHg and 173.0 ± 12.8 mmHg at month 6 after gene injection (~30mmHg and ~23mmHg lowerer than that in control animals, respectively, p <0.001). (3) Before the rats were sacrificed, cardiac function tests with Pressure-Volume System showed that maximum intracardiac pressure was 202.1 ± 30.0 & 209.1 ± 17.1mmHg in two gene-treated rats, respectively, significantly lower than control (241.2 ± 18.2mmHg, p <0.01) and cardiac output in treatment rats were significantly higher than control (p<0.05). (4) Interestingly, atrial natriuretic peptide (ANP) mRNA were up-regulated 6–14 folds respectively in myocardium of 2J2 and 2C11 groups; furthermore, C-type receptor mRNA of ANP was increased in heart, lung, kidney and aorta. (5) in cultured atrial cells (HLB2G5), exogenous EETs stimulated ANP production. In conclusions, for first time our data indicates overexpression of CYP2J2 or CYP2C11 could prevent development of hypertension in SHR, improve cardiac functions, which may involve up-regulating ANP expression and its receptors in target tissues, which suppresses collagen deposition and cardiovascular remodeling.

Download Full-text

Contribution of Heme Oxygenase 2 to Blood Pressure Regulation in Response to Swimming Exercise and Detraining in Spontaneously Hypertensive Rats

Medical Science Monitor ◽

10.12659/msm.908992 ◽

2018 ◽

Vol 24 ◽

pp. 5851-5859 ◽

Cited By ~ 2

Author(s):

Emine Kilic-Toprak ◽

Ozgen Kilic-Erkek ◽

Gulcin Abban-Mete ◽

Vildan Caner ◽

Ikbal Cansu Baris ◽

...

Keyword(s):

Blood Pressure ◽

Heme Oxygenase ◽

Spontaneously Hypertensive Rats ◽

Blood Pressure Regulation ◽

Swimming Exercise ◽

Pressure Regulation ◽

Hypertensive Rats ◽

Spontaneously Hypertensive

Download Full-text

Cytochrome P450 1B1 contributes to increased blood pressure and cardiovascular and renal dysfunction in spontaneously hypertensive rats

Cardiovascular Drugs and Therapy ◽

10.1007/s10557-014-6510-4 ◽

2014 ◽

Vol 28 (2) ◽

pp. 145-161 ◽

Cited By ~ 15

Author(s):

Brett L. Jennings ◽

David E. Montanez ◽

Michael E. May ◽

Anne M. Estes ◽

Xiao R. Fang ◽

...

Keyword(s):

Blood Pressure ◽

Cytochrome P450 ◽

Renal Dysfunction ◽

Spontaneously Hypertensive Rats ◽

Hypertensive Rats ◽

Spontaneously Hypertensive ◽

Cytochrome P450 1B1

Download Full-text

Functional Expression of Human Heme Oxygenase-1 Gene in Renal Structure of Spontaneously Hypertensive Rats

Experimental Biology and Medicine ◽

10.1177/15353702-0322805-04 ◽

2003 ◽

Vol 228 (5) ◽

pp. 454-458 ◽

Cited By ~ 11

Author(s):

Alvin I. Goodman ◽

Shou Quan ◽

Liming Yang ◽

Arika Synghal ◽

Nader G. Abraham

Keyword(s):

Blood Pressure ◽

Heme Oxygenase ◽

Spontaneously Hypertensive Rats ◽

Rat Kidney ◽

Functional Expression ◽

Heme Oxygenase 1 ◽

Thick Ascending Limb ◽

Bile Pigments ◽

Hypertensive Rats ◽

Spontaneously Hypertensive

Heme oxygenase (HO), by catabolizing heme to bile pigments, regulates the levels and activity of cellular hemoprotein and HO activity. We examined the effect of delivery of the human HO-1 gene on cellular heme in renal tissue using a retroviral vector. We used a single intracardiac injection of the concentrated infectious viral particles in 5-day-old spontaneously hypertensive rats; 25 were transduced with empty vector and 25 were transduced with the human HO-1 gene. Functional expression of human and rat HO-1 was measured after 2 and 4 weeks. Reverse transcription polymerase chain reaction showed that human HO-1 mRNA was expressed as early as 2 weeks, with the highest levels in the kidney. Western blot analysis showed distribution of human HO-1 protein in rat kidney structures, predominantly in the thick ascending limb of the loop of Henle as well as in proximal tubules and preglomerular arterioles. These areas also demonstrated higher HO activity as measured by increased conversion of heme to bilirubin and carbon monoxide. Functional expression of the human HO-1 gene was associated with a decrease in blood pressure in 4- and 8-week-old spontaneously hypertensive rats. Compared with nontransduced rats, human HO-1 gene overexpression in transduced rats was associated with a 35% decrease in urinary 20-hydroxyeicosatetraenoic acid, a potent vasoconstrictor and an inhibitor of tubular Na+ transport, which may be related to the decrease in blood pressure.

Download Full-text

Reconstitution of autophagy ameliorates vascular function and arterial stiffening in spontaneously hypertensive rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00227.2019 ◽

2019 ◽

Vol 317 (5) ◽

pp. H1013-H1027 ◽

Cited By ~ 6

Author(s):

Cameron G. McCarthy ◽

Camilla F. Wenceslau ◽

Fabiano B. Calmasini ◽

Nicole S. Klee ◽

Michael W. Brands ◽

...

Keyword(s):

Blood Pressure ◽

Vascular Function ◽

Spontaneously Hypertensive Rats ◽

Cellular Aging ◽

Experimental Hypertension ◽

Dependent Manner ◽

Vascular Aging ◽

Hypertensive Rats ◽

Spontaneously Hypertensive ◽

Autophagic Activity

Insufficient autophagy has been proposed as a mechanism of cellular aging, as this leads to the accumulation of dysfunctional macromolecules and organelles. Premature vascular aging occurs in hypertension. In fact, many factors that contribute to the deterioration of vascular function as we age are accelerated in clinical and experimental hypertension. Previously, we have reported decreased autophagy in arteries from spontaneously hypertensive rats (SHRs); however, the effects of restoring autophagic activity on blood pressure and vascular function are currently unknown. We hypothesized that reconstitution of arterial autophagy in SHRs would decrease blood pressure and improve endothelium-dependent relaxation. We treated 14- to 18-wk-old Wistar rats ( n = 7 vehicle and n = 8 trehalose) and SHRs ( n = 7/group) with autophagy activator trehalose (2% in drinking water) for 28 days. Blood pressure was measured by radiotelemetry, and vascular function and structure were measured in isolated mesenteric resistance arteries (MRAs) using wire and pressure myographs, respectively. Treatment with trehalose had no effect on blood pressure in SHRs; however, isolated MRAs presented enhanced relaxation to acetylcholine, in a cyclooxygenase- and reactive oxygen species-dependent manner. Similarly, trehalose treatment shifted the relaxation to the Rho kinase (ROCK) inhibitor Y-27632 to the right, indicating reduced ROCK activity. Finally, trehalose treatment decreased arterial stiffness as indicated by the slope of the stress-strain curve. Overall these data indicate that reconstitution of arterial autophagy in SHRs improves endothelial and vascular smooth muscle function, which could synergize to prevent stiffening. As a result, restoration of autophagic activity could be a novel therapeutic for premature vascular aging in hypertension. NEW & NOTEWORTHY This work supports the concept that diminished arterial autophagy contributes to premature vascular aging in hypertension and that therapeutic reconstitution of autophagic activity can ameliorate this phenotype. As vascular age is a new clinically used index for cardiovascular risk, understanding this mechanism may assist in the development of new drugs to prevent premature vascular aging in hypertension. Listen to this article’s corresponding podcast at https://ajpheart.podbean.com/e/behind-the-bench-episode-one-cam-squared/ .

Download Full-text

Transfer of the Human Heme Oxygenase-1 Gene Decreases Blood Pressure and Promotes Growth in Spontaneously Hypertensive Rats

Hypertension ◽

10.1161/hyp.36.suppl_1.730 ◽

2000 ◽

Vol 36 (suppl_1) ◽

pp. 730-730

Author(s):

Hatem E Sabaawy ◽

Fan Zhang ◽

Alberto Nasjletti ◽

Michal Laniado-Schwartzman ◽

Nader G Abraham

Keyword(s):

Blood Pressure ◽

Heme Oxygenase ◽

Spontaneously Hypertensive Rats ◽

Body Weight Gain ◽

Retroviral Vector ◽

Left Ventricular ◽

Intraluminal Pressure ◽

Heme Oxygenase 1 ◽

Hypertensive Rats ◽

Spontaneously Hypertensive

P203 Heme oxygenase (HO) catalyzes the conversion of heme to biliverdin, free iron and carbon monoxide (CO). Both heme and CO have been implicated in the regulation of vascular tone. We report the successful cloning of the human HO-1 cDNA (HHO-1) into a LXSN retroviral vector (LSN-HHO-1). A single intra-left ventricular delivery of 1×10 10 pfu/ml of LSN-HHO-1 to 5-day-old spontaneously hypertensive rats (SHR; n = 32) resulted in extended expression of the human HO-1 (mRNA and protein) in several tissues, including the kidney, liver, spleen, lung, heart, brain and aorta. The expression of HHO-1 was associated with a 2-3 fold increase in HO activity in these tissues. Mean blood pressure (MBP) of SHR injected with LSN-HHO-1 was significantly lower than that of SHR injected with the control empty vector LXSN, by 4 weeks of age (144±4.6 mmHg vs 164.8±6.5 mmHg, n=32, * p <0.01). SHR treated with LSN-HHO-1 demonstrated a consistent reduction in MBP of ≈20 ± 4 mmHg when compared with the control LXSN injected SHR throughout the 20 weeks of the experiment. Administration of the HO inhibitor, stannic mesoporphyrin (Sn MP), to LSN-HHO-1-treated SHR resulted in a 15 to 18 mmHg rise of MBP, further suggesting that increased HO expression underlie, at least in part, the blood pressure lowering effect of LSN-HHO-1. Rats expressing HHO-1 showed significant reduction in the urinary excretion of the vasoconstrictor cytochrome P-450 arachidonate metabolite, 20-HETE. Moreover, gracilis muscle arterioles (≈ 55μm in diameter) isolated from HHO-1 transgenic SHR showed less contractile responses to increased intraluminal pressure than vessels isolated from LXSN-treated SHR; this effect was reversed by the addition of SnMP. Interestingly, HHO-1 transgenic rats showed significant proportionate increase in somatic growth, i.e., nose to tail length, fibula length and body weight gain. These studies demonstrate that delivery of the human HO-1 gene by a retroviral vector results in permanent expression of HHO-1, long-term reduction in blood pressure together with growth promoting activity in the SHR.

Download Full-text