Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular remodeling is the result of a close interplay of changes in vascular tone and structure. In this review, the role of angiotension-converting enzyme (ACE) and the impact of ACE inhibition on vascular remodeling processes during vascular injury and restenosis, hypertension, atherosclerosis, and aneurysm formation are discussed. The role of ACE and angiotensin II (Ang II) in neointimal thickening has been firmly established by animal studies and is mediated by Ang II type 1 (AT(1)) receptor signaling events via monocyte chemoattractant protein-1 and NAD(P)H oxidase. ACE and Ang II are involved in the remodeling of large and resistance arteries during hypertension; here, cell proliferation and matrix remodeling are also regulated by signaling events downstream of the AT(1) receptor. In atherosclerosis, Ang II is involved in the inflammatory and tissue response, mediated by various signaling pathways downstream of the AT(1) receptor. Although ACE inhibition has been shown to inhibit atherosclerotic processes in experimental animal models, results of large clinical trials with ACE inhibitors were not conclusive. Remodeling of vessel dimensions and structure during aneurysm formation is counteracted by ACE inhibition. Here, a direct effect of ACE inhibitors on matrix metalloproteinase activity has to be considered as part of the working mechanism. The role of ACE2 in vascular remodeling has yet to be established; however, ACE2 has been shown to be associated with vascular changes in hypertension and atherosclerosis.
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PMID:Angiotensin-converting enzyme and vascular remodeling. 1776 34

Despite the dramatic decline of rheumatic heart disease over the past 5 decades, there has not been a concordant decline in the prevalence of valvular heart disease. Degenerative aortic valve disease (DAVD) has become the most common cause of valvular heart disease in the Western world, causing significant morbidity and mortality. No longer considered a benign consequence of aging, valve calcification is the result of an active process that, much like atherosclerotic vascular disease, is preceded by basement membrane disruption, inflammatory cell infiltration, and lipid deposition and is associated with diabetes, hypercholesterolemia, hypertension, and tobacco use. These realizations, in addition to pathological insights gained from emerging imaging modalities, have lead to the exploration of a variety of therapeutic interventions to delay or prevent the progression of DAVD. Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, angiotensin-converting enzyme, and matrix metalloproteinase have all been studied as potential disease modifiers. Moreover, tissue engineering, aided by emerging stem cell technology, holds immense potential for the treatment of valvular heart disease as adjuncts to surgical interventions. Here we review the epidemiology and pathophysiology of DAVD, in addition to highlighting emerging therapeutic interventions for this growing problem.
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PMID:Insights into degenerative aortic valve disease. 1838 46

It is now becoming apparent that dynamic changes occur within the interstitium that directly contribute to adverse myocardial remodeling following myocardial infarction (MI), with hypertensive heart disease and with intrinsic myocardial disease such as cardiomyopathy. Furthermore, a family of matrix proteases, the matrix metalloproteinases (MMPs) and the tissue inhibitors of MMPs (TIMPs), has been recognized to play an important role in matrix remodeling in these cardiac disease states. The purpose of this review is fivefold: 1) to examine and redefine the myocardial matrix as a critical and dynamic entity with respect to the remodeling process encountered with MI, hypertension, or cardiomyopathic disease; 2) present the remarkable progress that has been made with respect to MMP/TIMP biology and how it relates to myocardial matrix remodeling; 3) to evaluate critical translational/clinical studies that have provided a cause-effect relationship between alterations in MMP/TIMP regulation and myocardial matrix remodeling; 4) to provide a critical review and analysis of current diagnostic, prognostic, and pharmacological approaches that utilized our basic understanding of MMP/TIMPs in the context of cardiac disease; and 5) most importantly, to dispel the historical belief that the myocardial matrix is a passive structure and supplant this belief that the regulation of matrix protease pathways such as the MMPs and TIMPs will likely yield a new avenue of diagnostic and therapeutic strategies for myocardial remodeling and the progression to heart failure.
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PMID:Myocardial matrix remodeling and the matrix metalloproteinases: influence on cardiac form and function. 1792 85

The purpose of this work was to compare the effects of hypertension and hypercholesterolemia on carotid endothelial function, structure, and vasa vasorum density. Seventeen pigs were randomized to a 12-week normal diet without (n=5), or with renovascular hypertension (HT; n=6), or to a high cholesterol diet (HC; n=6). Carotid arteries were studied by organ chambers (endothelial function) and microcomputed tomography (vasa vasorum), and tissue was processed for Sirius red staining and immunoblotting (vascular endothelium growth factor, endostatin, matrix metalloproteinase-9, and matrix metalloproteinase-2). HC and HT showed reduced vasodilation to acetylcholine as compared with controls, but HT also had a lower response to sodium nitroprusside. In addition, HT showed a higher content of organized collagen fibers and increased intima-media thickness. Vasa vasorum density was increased in HC but not in HT. Both HT and HC showed a proangiogenetic biochemical milieu (higher vascular endothelium growth factor, matrix metalloproteinases, and lower endostatin), but this was more pronounced in HC. Both hypertension and hypercholesterolemia induce endothelial dysfunction in the carotid artery. However, hypertension is also associated with greater fibrosis and vascular wall thickening, which might impair endothelium-independent vasorelaxation and vasa vasorum growth. Hypercholesterolemia is, in turn, associated with vasa vasorum neovascularization. These data suggest that carotid atherosclerosis can evolve through different mechanisms in relation to different risk factors.
Hypertension 2007 Dec
PMID:Hypertension and hypercholesterolemia differentially affect the function and structure of pig carotid artery. 1796 2

Extracellular superoxide dismutase (SOD) contributes only a small fraction to total SOD activity in the normal heart but is strategically located to scavenge free radicals in the extracellular compartment. To examine the physiological significance of extracellular SOD in the response of the heart to hemodynamic stress, we studied the effect of extracellular SOD deficiency on transverse aortic constriction (TAC)-induced left ventricular remodeling. Under unstressed conditions extracellular SOD deficiency had no effect on myocardial total SOD activity, the ratio of glutathione:glutathione disulfide, nitrotyrosine content, or superoxide anion production but resulted in small but significant increases in myocardial fibrosis and ventricular mass. In response to TAC for 6 weeks, extracellular SOD-deficient mice developed more severe left ventricular hypertrophy (heart weight increased 2.56-fold in extracellular SOD-deficient mice as compared with 1.99-fold in wild-type mice) and pulmonary congestion (lung weight increased 2.92-fold in extracellular SOD-deficient mice as compared with 1.84-fold in wild-type mice). Extracellular SOD-deficient mice also had more ventricular fibrosis, dilation, and a greater reduction of left ventricular fractional shortening and rate of pressure development after TAC. TAC resulted in greater increases of ventricular collagen I, collagen III, matrix metalloproteinase-2, matrix metalloproteinase-9, nitrotyrosine, and superoxide anion production. TAC also resulted in a greater decrease of the ratio of glutathione:glutathione disulfide in extracellular SOD-deficient mice. The finding that extracellular SOD deficiency had minimal impact on myocardial overall SOD activity but exacerbated TAC induced myocardial oxidative stress, hypertrophy, fibrosis, and dysfunction indicates that the distribution of extracellular SOD in the extracellular space is critically important in protecting the heart against pressure overload.
Hypertension 2008 Jan
PMID:Extracellular superoxide dismutase deficiency exacerbates pressure overload-induced left ventricular hypertrophy and dysfunction. 1802 92

Beneficial effects of thiazolidinediones, peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, on cardiovascular injuries have been reported. However, the effects of these agonists on left ventricular (LV) hypertrophy have not been clarified. To investigate whether pioglitazone improves LV hypertrophy, we used 32-week-old stroke-prone spontaneously hypertensive rats (SHR-SP) that had been treated or not treated with pioglitazone (10 mg/kg/day) for 8 weeks, and Wistar Kyoto rats (WKY). We evaluated LV geometry by echocardiography; myocyte hypertrophy, tissue fibrosis, and appearance of myofibroblasts by histological examination; mRNA expression by real-time polymerase chain reaction (PCR); protein expression by Western blot; activities of matrix metalloproteinase (MMP) by zymography; and production of reactive oxygen species (ROS) by electron spin resonance spectroscopy or thiobarbituric acid reactive substances (TBARS). SHR-SP showed concentric hypertrophy of the LV, but WKY did not. The myocyte diameter, fraction of tissue fibrosis, and number of myofibroblasts were greater in SHR-SP. mRNA expressions of collagen type I and type III, tissue growth factor (TGF)-beta1, and brain natriuretic peptide (BNP); protein expression of connective tissue growth factor (CTGF); activities of MMP2 and MMP9; and ROS were increased in SHR-SP. Pioglitazone did not decrease blood pressure, but partially normalized LV geometry in addition to decreasing myocyte diameter, interstitial fibrosis and number of myofibroblasts; mRNA levels of collagen type I and BNP; MMP2 activity; and protein level of CTGF. However, the mRNA level of collagen type III and TGF-beta1, MMP9 activity, and ROS production were not improved. In conclusion, pioglitazone reversed the concentric LV remodeling independently from blood pressure or oxidative stress in chronic hypertension.
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PMID:Beneficial effects of pioglitazone on left ventricular hypertrophy in genetically hypertensive rats. 1803 80

Although cardiac synchronization is important in maintaining myocardial performance, the mechanism of dys-synchronization in ailing to failing myocardium is unclear. It is known that the cardiac myocyte contracts and relaxes individually; however, it synchronizes only when connected to one another by low resistance communications called gap junction protein (connexins) and extra cellular matrix (ECM). Therefore, the remodeling of connexins and ECM in heart failure plays an important role in cardiac conduction, synchronization and arrhythmias. This review for the first time addresses the role of systemic accumulation of homocysteine (Hcy) in vasospasm, pressure and volume overload heart failure, hypertension and cardiac arrhythmias. The attenuation of calcium-dependent mitochondrial (mt), endothelial and neuronal nitric oxide synthase (mtNOS, eNOS and nNOS) by Hcy plays a significant role in cardiac arrhythmias. The signal transduction mechanisms in Hcy-induced matrix metalloproteinase (MMP) activation in cardiac connexin remodeling are discussed.
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PMID:Cardiac dys-synchronization and arrhythmia in hyperhomocysteinemia. 1804 55

Suppressed parasympathetic nervous system (PSNS) function has been found in a variety of cardiovascular diseases, such as hypertension, heart failure, and diabetes. However, whether impaired PSNS function plays a significant role in ventricular dysfunction remains to be investigated. Cardiac regulation by the PSNS is primarily mediated by the M(2) muscarinic acetylcholine receptor (M(2)-AChR). In this study, we tested the hypothesis that lack of M(2)-AChR-mediated PSNS function may adversely impact cardiac ventricular function. Using M(2)-AChR knockout (KO) and wild-type (WT) mice, we found that the basal levels of heart rate and left ventricular function were similar in M(2)-AChR KO and WT mice. A bolus injection of isoproterenol (Iso) induced a greater increase in heart rate in M(2)-AChR KO mice than in WT mice. However, the responses of change in pressure over time (dP/dt) to Iso were similar in the two groups. After chronic infusion with Iso for 1 wk, the baseline values of left ventricular function were increased to similar extents in M(2)-AChR KO and WT mice. However, the M(2)-AChR KO mice exhibited impaired ventricular function, indicated as attenuated dP/dt and increased end-diastolic pressure, during an increase in cardiac afterload induced by a bolus injection of phenylephrine. Furthermore, chronic Iso infusion significantly increased matrix metalloproteinase (MMP) activity in the heart in M(2)-AChR KO mice. In primary culture of mixed neonatal rat cardiac fibroblast and cardiomyocytes, cotreatment with muscarinic agonist bethanechol reversed phenylephrine-induced increase in MMP-9 activation. These data suggest that M(2)-AChR may mediate an inhibitory regulation on MMP function. The overall results from this study suggest that M(2)-AChR-mediated PSNS function may provide cardiac protection. Lack of this protective mechanism will increase the susceptibility of the heart to cardiac stresses.
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PMID:Deficiency of M2 muscarinic acetylcholine receptors increases susceptibility of ventricular function to chronic adrenergic stress. 1805 17

Oxidative stress plays an important role in the development of cardiac remodeling after myocardial infarction (MI), but the sources of oxidative stress remain unclear. We investigated the role of Nox2-containing reduced nicotinamide-adenine dinucleotide phosphate oxidase in the development of cardiac remodeling after MI. Adult Nox2(-/-) and matched wild-type (WT) mice were subjected to coronary artery ligation and studied 4 weeks later. Infarct size after MI was similar in Nox2(-/-) and WT mice. Nox2(-/-) mice exhibited significantly less left ventricular (LV) cavity dilatation and dysfunction after MI than WT mice (eg, echocardiographic LV end-diastolic volume: 75.7+/-5.8 versus 112.4+/-12.3 microL; ejection fraction: 41.6+/-3.7 versus 32.9+/-3.2%; both P<0.05). Similarly, in vivo LV systolic and diastolic functions were better preserved in Nox2(-/-) than WT mice (eg, LV dP/dt(max): 7969+/-385 versus 5746+/-234 mm Hg/s; LV end-diastolic pressure: 12.2+/-1.3 versus 18.0+/-1.8 mm Hg; both P<0.05). Nox2(-/-) mice exhibited less cardiomyocyte hypertrophy, apoptosis, and interstitial fibrosis; reduced increases in expression of connective tissue growth factor and procollagen 1 mRNA; and smaller increases in myocardial matrix metalloproteinase-2 activity than WT mice. These data suggest that the Nox2-containing reduced nicotinamide-adenine dinucleotide phosphate oxidase contributes significantly to the processes underlying adverse cardiac remodeling and contractile dysfunction post-MI.
Hypertension 2008 Feb
PMID:Involvement of Nox2 NADPH oxidase in adverse cardiac remodeling after myocardial infarction. 1818 Apr 3

Useful drug therapy for inhibiting the extension of an aortic aneurysm or promoting its involution has not yet been established. Hypertension is a known risk factor for extension of an aortic aneurysm. However, on a cellular level it is believed that activation of nuclear factor (NF)-kappaB and matrix metalloproteinase (MMP) is involved in the extension of an aortic aneurysm. Nifedipine has been evaluated in a rat model of aortic aneurysm and it was found to inhibit activation of MMP and extension of the aortic aneurysm. Nifedipine also inhibited activation of NF-kappaB and these effects were independent of the antihypertensive effect of the drug. With antihypertensive and vasculoprotective effects and inhibitory actions on activation of NF-kappaB and MMP, nifedipine has potential to be a useful option in the drug treatment of patients with aortic aneurysm.
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PMID:[Effect of nifedipine on organ protection: potential application in patients with aortic aneurysm]. 1820 Jul 78


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