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Curt D. Sigmund - One of the best experts on this subject based on the ideXlab platform.
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β-Arrestin–Biased Agonist Targeting the Brain AT1R (Angiotensin II Type 1 Receptor) Increases Aversion to Saline and Lowers Blood Pressure in Deoxycorticosterone Acetate–Salt Hypertension
Hypertension (Dallas Tex. : 1979), 2020Co-Authors: Mario Zanaty, Justin L. Grobe, Fernando A.c. Seara, Pablo Nakagawa, Guorui Deng, Natalia M. Mathieu, Kirthikaa Balapattabi, Sadashiva S. Karnik, Curt D. SigmundAbstract:Activation of central AT1Rs (angiotensin type 1 receptors) is required for the increased blood pressure, polydipsia, and salt intake in Deoxycorticosterone Acetate (DOCA)–salt hypertension. TRV1200...
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β arrestin biased agonist targeting the brain at1r angiotensin ii type 1 receptor increases aversion to saline and lowers blood pressure in Deoxycorticosterone Acetate salt hypertension
Hypertension, 2020Co-Authors: Justin L. Grobe, Mario Zanaty, Fernando A.c. Seara, Pablo Nakagawa, Guorui Deng, Natalia M. Mathieu, Kirthikaa Balapattabi, Sadashiva S. Karnik, Curt D. SigmundAbstract:Activation of central AT1Rs (angiotensin type 1 receptors) is required for the increased blood pressure, polydipsia, and salt intake in Deoxycorticosterone Acetate (DOCA)–salt hypertension. TRV1200...
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protective role for tissue inhibitor of metalloproteinase 4 a novel peroxisome proliferator activated receptor γ target gene in smooth muscle in Deoxycorticosterone Acetate salt hypertension
Hypertension, 2016Co-Authors: Pimonrat Ketsawatsomkron, Henry L. Keen, Deborah R. Davis, Madeliene Stump, Aline M. Hilzendeger, Justin L. Grobe, Frank M. Faraci, Michael T De Silva, Curt D. SigmundAbstract:Loss of peroxisome proliferator-activated receptor-γ (PPARγ) function causes hypertension, whereas its activation lowers blood pressure. Evidence suggests that these effects may be attributable to PPARγ activity in the vasculature. However, the specific transcriptional targets of PPARγ in vessels remain largely unidentified. In this study, we examined the role of smooth muscle PPARγ during salt-sensitive hypertension and investigated its transcriptional targets and functional effect. Transgenic mice expressing dominant-negative PPARγ (S-P467L) in smooth muscle cells were more prone to Deoxycorticosterone Acetate-salt-induced hypertension and mesenteric arterial dysfunction compared with nontransgenic controls. Despite similar morphometry at baseline, vascular remodeling in conduit and small arteries was enhanced in S-P467L after Deoxycorticosterone Acetate-salt treatment. Gene expression profiling in aorta and mesenteric arteries revealed significantly decreased expression of tissue inhibitor of metalloproteinase-4 (TIMP-4) in S-P467L. Expression of TIMP-4 was increased by Deoxycorticosterone Acetate-salt treatment, but this increase was ablated in S-P467L. Interference with PPARγ activity either by treatment with a PPARγ inhibitor, GW9662, or by expressing P467L PPARγ markedly suppressed TIMP-4 in primary smooth muscle cells. PPARγ binds to a PPAR response element (PPRE) in chromatin close to the TIMP-4 gene in smooth muscle cells, suggesting that TIMP-4 is a novel target of PPARγ. The interference with PPARγ and decrease in TIMP-4 were accompanied by an increase in total matrix metalloproteinase activity. PPARγ-mediated loss of TIMP-4 increased, whereas overexpression of TIMP-4 decreased smooth muscle cell migration in a scratch assay. Our findings highlight a protective mechanism induced by PPARγ in Deoxycorticosterone Acetate-salt treatment, establishing a novel mechanistic link between PPARγ and TIMP-4.
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Protective Role for Tissue Inhibitor of Metalloproteinase-4, a Novel Peroxisome Proliferator–Activated Receptor-γ Target Gene, in Smooth Muscle in Deoxycorticosterone Acetate–Salt Hypertension
Hypertension (Dallas Tex. : 1979), 2015Co-Authors: Pimonrat Ketsawatsomkron, Henry L. Keen, Deborah R. Davis, Madeliene Stump, T. Michael De Silva, Aline M. Hilzendeger, Justin L. Grobe, Frank M. Faraci, Curt D. SigmundAbstract:Loss of peroxisome proliferator-activated receptor-γ (PPARγ) function causes hypertension, whereas its activation lowers blood pressure. Evidence suggests that these effects may be attributable to PPARγ activity in the vasculature. However, the specific transcriptional targets of PPARγ in vessels remain largely unidentified. In this study, we examined the role of smooth muscle PPARγ during salt-sensitive hypertension and investigated its transcriptional targets and functional effect. Transgenic mice expressing dominant-negative PPARγ (S-P467L) in smooth muscle cells were more prone to Deoxycorticosterone Acetate-salt-induced hypertension and mesenteric arterial dysfunction compared with nontransgenic controls. Despite similar morphometry at baseline, vascular remodeling in conduit and small arteries was enhanced in S-P467L after Deoxycorticosterone Acetate-salt treatment. Gene expression profiling in aorta and mesenteric arteries revealed significantly decreased expression of tissue inhibitor of metalloproteinase-4 (TIMP-4) in S-P467L. Expression of TIMP-4 was increased by Deoxycorticosterone Acetate-salt treatment, but this increase was ablated in S-P467L. Interference with PPARγ activity either by treatment with a PPARγ inhibitor, GW9662, or by expressing P467L PPARγ markedly suppressed TIMP-4 in primary smooth muscle cells. PPARγ binds to a PPAR response element (PPRE) in chromatin close to the TIMP-4 gene in smooth muscle cells, suggesting that TIMP-4 is a novel target of PPARγ. The interference with PPARγ and decrease in TIMP-4 were accompanied by an increase in total matrix metalloproteinase activity. PPARγ-mediated loss of TIMP-4 increased, whereas overexpression of TIMP-4 decreased smooth muscle cell migration in a scratch assay. Our findings highlight a protective mechanism induced by PPARγ in Deoxycorticosterone Acetate-salt treatment, establishing a novel mechanistic link between PPARγ and TIMP-4.
Pingjin Gao - One of the best experts on this subject based on the ideXlab platform.
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Beta3 adrenergic receptor is involved in vascular injury in Deoxycorticosterone Acetate-salt hypertensive mice.
FEBS letters, 2016Co-Authors: Li-juan Sheng, Cheng-chao Ruan, Dong-rui Chen, Ling-ran Kong, Dingliang Zhu, Pingjin GaoAbstract:Beta3 adrenergic receptor (ADRB3) mediates vessel relaxation in the endothelium while it modulates lipolysis in the adipose tissue. However, the function and regulation mechanism of ADRB3 in the perivascular adipose tissue (PVAT), especially in hypertension, is still unclear. We show that ADRB3 protein is upregulated in the PVAT of Deoxycorticosterone Acetate-salt (DOCA-salt) hypertensive mice, with the characteristics of PVAT browning and increased uncoupling protein 1 (UCP1) expression. Inhibition of ADRB3 with selective antagonist SR59230A caused serious vascular injury in vivo, even though UCP1 expression was downregulated. ADRB3 protein was regulated by let-7b, which was decreased in the PVAT of the DOCA-salt group. These data reveal that ADRB3 in PVAT contributes to vascular function in the progression of hypertension.
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perivascular adipose tissue derived complement 3 is required for adventitial fibroblast functions and adventitial remodeling in Deoxycorticosterone Acetate salt hypertensive rats
Arteriosclerosis Thrombosis and Vascular Biology, 2010Co-Authors: Cheng-chao Ruan, Qizhi Chen, Jing Chen, Dingliang Zhu, Shujie Guo, Pingjin GaoAbstract:Objective— To examine the role of perivascular adipose tissue (PVAT)–derived factors in the regulation of adventitial fibroblast (AF) function in vitro and in vivo. Methods and Results— PVAT is an active component of blood vessels. Bioactive substances released from PVAT play regulatory roles in vascular function. However, their effects on vascular AFs remain unclear. PVAT-conditioned medium stimulated AF migration using a transwell technique, and differentiation was evaluated by α-smooth muscle–actin induction. We identified the secretome of PVAT by liquid chromatography–tandem mass spectrometry. One of the major secretory proteins in PVAT is complement 3 (C3). The C3 antagonist and neutralizing antibody attenuated PVAT-conditioned medium–induced AF migration and differentiation. Similar to PVAT-conditioned medium, C3 recombinant protein stimulated AF migration and differentiation. We demonstrated that the effects of PVAT-derived C3 were mediated by the c-Jun N-terminal kinase pathway. Moreover, we found morphological changes in perivascular adipocytes and increased expression of C3 in PVAT that was tightly associated with adventitial thickening and myofibroblast clustering around PVAT in Deoxycorticosterone Acetate–salt hypertensive rats. Conclusion— PVAT-derived C3 stimulated AF migration and differentiation via the c-Jun N-terminal kinase pathway. PVAT-derived C3 may contribute to adventitial remodeling in a Deoxycorticosterone Acetate–salt hypertensive model.
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Perivascular Adipose Tissue–Derived Complement 3 Is Required for Adventitial Fibroblast Functions and Adventitial Remodeling in Deoxycorticosterone Acetate–Salt Hypertensive Rats
Arteriosclerosis thrombosis and vascular biology, 2010Co-Authors: Cheng-chao Ruan, Qizhi Chen, Jing Chen, Dingliang Zhu, Shujie Guo, Pingjin GaoAbstract:Objective— To examine the role of perivascular adipose tissue (PVAT)–derived factors in the regulation of adventitial fibroblast (AF) function in vitro and in vivo. Methods and Results— PVAT is an active component of blood vessels. Bioactive substances released from PVAT play regulatory roles in vascular function. However, their effects on vascular AFs remain unclear. PVAT-conditioned medium stimulated AF migration using a transwell technique, and differentiation was evaluated by α-smooth muscle–actin induction. We identified the secretome of PVAT by liquid chromatography–tandem mass spectrometry. One of the major secretory proteins in PVAT is complement 3 (C3). The C3 antagonist and neutralizing antibody attenuated PVAT-conditioned medium–induced AF migration and differentiation. Similar to PVAT-conditioned medium, C3 recombinant protein stimulated AF migration and differentiation. We demonstrated that the effects of PVAT-derived C3 were mediated by the c-Jun N-terminal kinase pathway. Moreover, we found morphological changes in perivascular adipocytes and increased expression of C3 in PVAT that was tightly associated with adventitial thickening and myofibroblast clustering around PVAT in Deoxycorticosterone Acetate–salt hypertensive rats. Conclusion— PVAT-derived C3 stimulated AF migration and differentiation via the c-Jun N-terminal kinase pathway. PVAT-derived C3 may contribute to adventitial remodeling in a Deoxycorticosterone Acetate–salt hypertensive model.
Nen Chung Chang - One of the best experts on this subject based on the ideXlab platform.
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endothelin receptor blockade ameliorates renal injury by inhibition of rhoa rho kinase signalling in Deoxycorticosterone Acetate salt hypertensive rats
Journal of Hypertension, 2014Co-Authors: Tsung Ming Lee, Tun Hui Chung, Shinn Zong Lin, Nen Chung ChangAbstract:Purpose of review:Excessive production of fibrosis is a feature of hypertension-induced renal injury. Activation of RhoA/Rho-kinase (ROCK) axis has been shown in Deoxycorticosterone Acetate (DOCA)-salt hypertensive rats. We assessed whether selective endothelin receptor blockers can attenuate renal
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Endothelin receptor blockade ameliorates renal injury by inhibition of RhoA/Rho-kinase signalling in Deoxycorticosterone Acetate-salt hypertensive rats.
Journal of hypertension, 2014Co-Authors: Tsung Ming Lee, Tun Hui Chung, Shinn Zong Lin, Nen Chung ChangAbstract:Purpose of review:Excessive production of fibrosis is a feature of hypertension-induced renal injury. Activation of RhoA/Rho-kinase (ROCK) axis has been shown in Deoxycorticosterone Acetate (DOCA)-salt hypertensive rats. We assessed whether selective endothelin receptor blockers can attenuate renal
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cardiac sympathetic hyperinnervation in Deoxycorticosterone Acetate salt hypertensive rats
Clinical Science, 2012Co-Authors: Tsung Ming Lee, Nen Chung Chang, Chien Chang ChenAbstract:Sympathetic activities are elevated in the central SNSs (sympathetic nervous systems) of hypertensive animals, but it is not known whether sympathetic innervation is also elevated in the heart. Sympathetic hyper-responsiveness in hypertension may result from oxidative stress. The aim of the present study was to investigate sympathetic hyperinnervation in DOCA (Deoxycorticosterone Acetate)-salt hypertensive rats with established hypertension. At 4 weeks after the start of DOCA-salt treatment and uninephrectomization, male Wistar rats were randomized into three groups for 8 weeks: vehicle, NAC ( N -acetylcysteine) and triple therapy (hydralazine, hydrochlorothiazide and reserpine). DOCA-salt was associated with increased oxidant release. DOCA-salt produced concentric left ventricular hypertrophy and cardiomyocyte hypertrophy. Sympathetic hyperinnervation was observed in DOCA-salt rats, as assessed by myocardial noradrenaline levels, immunofluorescent analysis of tyrosine hydroxylase, growth-associated factor 43 and neurofilament and Western blotting and real-time quantitative RT–PCR (reverse transcription–PCR) of NGF (nerve growth factor). Arrhythmic scores during programmed stimulation in DOCA-salt rats were significantly higher than those in the control rats. Triple therapy, despite being effective on BP (blood pressure), offered neither attenuated cardiomyocyte hypertrophy nor anti-arrhythmia. The effects of DOCA-salt treatment on NGF expression, sympathetic hyperinnervation and arrhythmias were attenuated by NAC. Furthermore, the effects of NAC on NGF were abolished by administering BSO (L-buthionine sulfoximine), an inhibitor of glutamate–cysteine ligase. In conclusion, DOCA-salt treatment contributes to up-regulation of NGF proteins probably through a free radical-dependent pathway in a BP-independent manner. DOCA-salt rats treated with NAC attenuate sympathetic hyperinnervation and thus show a beneficial effect on arrhythmogenic response to programmed electrical stimulation.
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Effect of pravastatin on nephroprotection in Deoxycorticosterone Acetate-salt hypertensive rats
Journal of hypertension, 2009Co-Authors: Chih Sen Kang, Nen Chung Chang, Shen Tien Chang, Chih Chan Lin, Tsung Ming LeeAbstract:OBJECTIVE Endothelin-1 (ET-1) has been implicated in the pathogenesis of renal impairment. The current study was undertaken to assess the effect of pravastatin on the progression of renal impairment in Deoxycorticosterone Acetate (DOCA)-salt hypertensive rats. METHODS Four weeks after the start of DOCA-salt treatment and uninephrectomization, male Wistar rats were treated with one of the following therapies for 8 weeks: vehicle; a nonselective endothelin receptor antagonist bosentan; pravastatin; or hydralazine. RESULTS Treatment with bosentan or pravastatin was associated with reductions in blood pressure and renal medullary hydroxyproline content, and improvement in glomerular filtration rate, urinary protein excretion, macrophage infiltration, tubular injury, and vascular injury, but not glomerulosclerosis. The renal medullary ET-1 protein levels and preproET-1 mRNA assessed by western blotting and real-time quantitative reverse transcription-PCR were significantly decreased (both P < 0.001) in the pravastatin-treated rats compared with vehicle, which was also confirmed by immunohistochemical analysis. However, there were no significant differences of ET-1 levels in the renal cortex among the DOCA-salt groups. The nephroprotective effects of pravastatin were not associated with its antihypertensive action because hydralazine despite reducing blood pressure failed to improve renal function and disorder. CONCLUSION These results suggest a crucial role of renal endothelin system in the pathogenesis of renal functional and structural alterations in the DOCA-salt hypertensive rats. Pravastatin administration ameliorates the impairment of renal function and structures by attenuating medullary ET-1 expression, independent of systemic blood pressure.
Yasuo Matsumura - One of the best experts on this subject based on the ideXlab platform.
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Role of gp91phox-containing NADPH oxidase in the Deoxycorticosterone Acetate-salt-induced hypertension.
European journal of pharmacology, 2006Co-Authors: Aya Fujii, Masanori Takaoka, Mamoru Ohkita, Daisuke Nakano, Miyuki Katsuragi, Yukihiro Ohno, Yasuo MatsumuraAbstract:NADPH oxidase plays an important role in vascular oxidative stress in hypertensive diseases. We evaluated whether NADPH oxidase-dependent superoxide (O(2)(-)) production is involved in the Deoxycorticosterone Acetate (DOCA)-salt-induced hypertension, using mice which are genetically deficient in gp91phox, an NADPH oxidase subunit protein (gp91(-/-) mice). Two weeks after the DOCA-salt treatment, systolic blood pressure was significantly elevated in wild-type mice, but not in gp91(-/-) mice. After a 5-week treatment period, wild-type mice developed high blood pressure, with a systolic blood pressure of 127 +/- 3 mm Hg, compared with 107 +/- 4 mm Hg in gp91(-/-) mice. Aortic O(2)(-) production in wild-type DOCA-salt-treated mice was significantly higher than that in wild-type sham mice, whereas there were no significant differences in aortic O(2)(-) production between gp91(-/-) DOCA-salt-treated and sham mice. These findings suggest that vascular O(2)(-) overproduction via gp91phox-containing NADPH oxidase is one of the crucial factors in the development of DOCA-salt-induced hypertension.
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A proteasome inhibitor prevents vascular hypertrophy in Deoxycorticosterone Acetate-salt hypertensive rats.
Clinical and experimental pharmacology & physiology, 2001Co-Authors: Masanori Takaoka, Hisako Okamoto, Mamoru Ohkita, Makoto Itoh, Yutaka Kobayashi, Yasuo MatsumuraAbstract:1. In the present study, we investigated the potential of the proteasome inhibitor N-benzyloxycarbonyl-Ile-Glu(O-t-Bu)-Ala-leucinal (PSI) to prevent vascular hypertrophy induced by Deoxycorticosterone Acetate (DOCA) and salt in rats. 2. Vehicle (35% ethanol, 35% polyethylene glycol and 30% saline solution)-treated DOCA-salt rats developed marked hypertension at 4 weeks. Morphological studies on the rats given vehicle showed aortic hypertrophy, with a significant increase in wall thickness, wall area and wall-to-lumen ratio. A significant decrease in vascular wall hypertrophy was observed in PSI (3 mg/kg)-treated DOCA-salt rats. In addition, a marked increase in aortic endothelin (ET)-1 content was evident in vehicle-treated DOCA-salt rats compared with findings in sham-operated rats. A significant attenuation of this increase occurred in PSI-treated DOCA-salt rats. 3. These results indicate that PSI can prevent the vascular hypertrophy in DOCA-salt hypertensive rats and the effect is accompanied by suppression of ET-1 production in the aorta. We suggest that a proteasome-dependent proteolytic system has an important role in the development of vascular hypertrophy in cases of DOCA-salt-induced hypertension, possibly through the enhancement of ET-1 production in vascular tissues.
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exaggerated vascular and renal pathology in endothelin b receptor deficient rats with Deoxycorticosterone Acetate salt hypertension
Circulation, 2000Co-Authors: Yasuo Matsumura, Masanori Takaoka, Yutaka Kobayashi, Toshihiko Kuro, Fumiko Konishi, Jerry L Wessale, Terry J Opgenorth, Cheryl E Gariepy, Masashi YanagisawaAbstract:Background—Endothelin (ET)-1 plays an important role in the pathogenesis of Deoxycorticosterone Acetate (DOCA)-salt–induced hypertension. We evaluated the pathological role of ETB receptors in DOCA-salt–induced hypertension, cardiovascular hypertrophy, and renal damage by using the spotting-lethal (sl) rat, which carries a naturally occurring deletion in the ETB receptor gene. Methods and Results—Homozygous (sl/sl) rats exhibit abnormal development of neural crest–derived epidermal melanocytes and the enteric nervous system, and they do not live beyond 1 month because of intestinal aganglionosis and intestinal obstruction. The dopamine β-hydroxylase (DβH) promoter was used to direct ETB transgene expression in sl/sl rats to support normal enteric nervous system development. DβH-ETB sl/sl rats live into adulthood and are healthy, expressing ETB receptors in adrenal glands and other adrenergic neurons. When homozygous (sl/sl) and wild-type (+/+) rats, all of which were transgenic, were treated with DOCA-sal...
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A proteasome inhibitor lessens the increased aortic endothelin-1 content in Deoxycorticosterone Acetate-salt hypertensive rats
European journal of pharmacology, 1998Co-Authors: Hisako Okamoto, Masanori Takaoka, Mamoru Ohkita, Makoto Itoh, Mio Nishioka, Yasuo MatsumuraAbstract:Abstract Deoxycorticosterone Acetate (DOCA)-salt-treated rats developed marked hypertension after 4 weeks with an increase in aortic endothelin-1. Treatment of DOCA-salt hypertensive rats with a proteasome inhibitor, N-benzyloxycarbonyl-Ile-Glu(O-t-Bu)-Ala-leucinal, significantly reduced the elevation in systolic blood pressure and the effect was accompanied by a decrease in aortic endothelin-1 content. Thus, a proteasome-dependent proteolytic pathway appears to play an important role in the enhanced production of endothelin-1 in blood vessels and the consequent increase in blood pressure in this model of hypertension.
Joseph Fomusi Ndisang - One of the best experts on this subject based on the ideXlab platform.
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heme arginate suppresses cardiac lesions and hypertrophy in Deoxycorticosterone Acetate salt hypertension
Experimental Biology and Medicine, 2009Co-Authors: Ashok Jadhav, Joseph Fomusi NdisangAbstract:In hypertension, elevated levels of oxidative/inflammatory mediators including nuclear factor kappaB (NF-κB), activating protein (AP-1), c-Jun-NH2-terminal kinase (JNK), and cell-regulatory proteins such as transforming growth factor beta (TGF-β), trigger the mobilization of extracellular matrix (ECM) leading to fibrosis, hypertrophy and impairment of cardiac function. Although the heme oxygenase (HO) system is cytoprotective, its effects on cardiac fibrosis and hypertrophy in Deoxycorticosterone Acetate (DOCA-salt) hypertension are not completely elucidated. Here, we report cardioprotection by the HO inducer, heme arginate against histopathological lesions in DOCA-hypertension. Treatment with heme arginate restored physiological blood pressure, and abated cardiac hypertrophy (3.75 ± 0.12 vs. 3.19 ± 0.09 g/kg body wt; n =16, P < 0.01), left-to-right ventricular ratio (6.67 ± 0.62 vs. 4.39 ± 0.63; n = 16, P < 0.01), left ventricular mass (2.48 ± 0.14 vs. 2.01 ± 0.09 g/kg body wt; n = 16, P < 0.01) and left...
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heme arginate suppresses cardiac lesions and hypertrophy in Deoxycorticosterone Acetate salt hypertension
Experimental Biology and Medicine, 2009Co-Authors: Ashok Jadhav, Joseph Fomusi NdisangAbstract:In hypertension, elevated levels of oxidative/inflammatory mediators including nuclear factor kappaB (NF-κB), activating protein (AP-1), c-Jun-NH2-terminal kinase (JNK), and cell-regulatory proteins such as transforming growth factor beta (TGF-β), trigger the mobilization of extracellular matrix (ECM) leading to fibrosis, hypertrophy and impairment of cardiac function. Although the heme oxygenase (HO) system is cytoprotective, its effects on cardiac fibrosis and hypertrophy in Deoxycorticosterone Acetate (DOCA-salt) hypertension are not completely elucidated. Here, we report cardioprotection by the HO inducer, heme arginate against histopathological lesions in DOCA-hypertension. Treatment with heme arginate restored physiological blood pressure, and abated cardiac hypertrophy (3.75 ± 0.12 vs. 3.19 ± 0.09 g/kg body wt; n =16, P < 0.01), left-to-right ventricular ratio (6.67 ± 0.62 vs. 4.39 ± 0.63; n = 16, P < 0.01), left ventricular mass (2.48 ± 0.14 vs. 2.01 ± 0.09 g/kg body wt; n = 16, P < 0.01) and left...