Protease-activated receptor and endothelial-myocyte uncoupling in chronic heart failure (original) (raw)
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Role of matrix metalloproteinase-9 in endothelial apoptosis in chronic heart failure in mice
Journal of Applied Physiology, 2005
Accumulation of oxidized extracellular matrix (ECM) between endothelium and muscle is an important risk factor in the endothelium-myocytes (E-M) uncoupling in congestive heart failure (CHF). Although ventricular remodeling is accompanied by increased matrix metalloproteinase-9 (MMP-9) activity, it is unclear whether MMP-9 plays a role in endothelial apoptosis in chronic volume overload CHF. We tested the hypothesis that in chronic volume overload, myocardial dysfunction involves endocardial endothelial (EE) apoptosis in response to MMP-9 activation, ECM accumulation and E-M uncoupling. Methods: Arteriovenous fistula (AVF) was created in control (FVB/NJ, AVF group) and MMP-9 knockout (FVB.Cg-Mmp9 tm1Tvu /J, MMP9KO+AVF group) mice. Sham surgery was used as control. Mice were grouped as follows: WT, n=3 (sham control), MMP9KO, n=3 (sham), AVF, n=3, and MMP9KO+AVF (n=3). Heart function was analyzed by M-mode and Doppler echocardiography, and with a pressure tipped Millar catheter placed in the left ventricle (LV) of anesthetized mice 8 wks after AVF. Apoptosis was detected by measuring caspase-3, TUNEL and CD-31 by immuno-labeling. Protease activated receptors-1 (PAR-1), connexin-43 and a disintegrin and metalloproteinase-12 (ADAM-12) expression were measured by Western blot analyses. MMP-2 and MMP-9 expression were measured by Q-RT-PCR. Results: Compared to
Nitrosative stress and pharmacological modulation of heart failure
Trends in Pharmacological Sciences, 2005
Dysregulation of nitric oxide (NO) and increased oxidative and nitrosative stress are implicated in the pathogenesis of heart failure. Peroxynitrite is a reactive oxidant that is produced from the reaction of nitric oxide with superoxide anion and impairs cardiovascular function through multiple mechanisms, including activation of matrix metalloproteinases (MMPs) and nuclear enzyme poly (ADP-ribose) polymerase (PARP). Recent studies suggest that the neutralization of peroxynitrite or pharmacological inhibition of MMPs and PARP are promising new approaches in the experimental therapy of various forms of myocardial injury. In this article, the role of nitrosative stress and downstream mechanisms, including activation of MMPs and PARP, in various forms of heart failure are discussed and novel emerging therapeutic strategies offered by neutralization of peroxynitrite and inhibition of MMPs and PARP in these pathophysiological conditions are reviewed. Role of increased oxidative stress in heart failure Acute heart failure and chronic heart failure (CHF) are major causes of hospitalization, morbidity and mortality worldwide. Several different mechanisms can lead to cardiac pump failure (Figure 1). These mechanisms result in a mismatch between the load applied to the heart and the energy needed for contraction, which leads to reduced contractile efficiency (Figure 1). The pathomechanism of heart failure is complex and involves the activation of numerous secondary pathways (e.g. pathways involving neurohormones, cytokines, oxidative stress and nitrosative stress), which leads to: (i) abnormalities in various signaling processes, cardiac receptors and Ca 2+ homeostasis; (ii) contractile protein desensitization; and (iii) endothelial dysfunction. The resulting structural alterations can involve cardiac and vascular remodeling with hypertrophy, fibrosis, cardiac dilation and myocardial necrosis. The adverse remodeling and increased peripheral resistance further aggravate heart failure (Figure 1). Experimental and clinical studies demonstrate increased production of reactive oxygen species (ROS) in the pathogenesis of acute heart failure and CHF. Plasma malondialdehyde-like activity (MDA), a marker of lipid peroxidation, is increased in patients with ischemic and nonischemic dilated cardiomyopathy, and has an inverse relationship with ejection fraction (an Corresponding author: Pacher, P.
Circulation Research, 2005
Cytokine and extracellular matrix (ECM) homeostasis are distinct systems that are each dysregulated in heart failure. Here we show that tissue inhibitor of metalloproteinase (TIMP)-3 is a critical regulator of both systems in a mouse model of left ventricular (LV) dilation and dysfunction. Timp-3 Ϫ/Ϫ mice develop precipitous LV dilation and dysfunction reminiscent of dilated cardiomyopathy (DCM), culminating in early onset of heart failure by 6 weeks, compared with wild-type aortic-banding (AB). Timp-3 deficiency resulted in increased TNF␣ converting enzyme (TACE) activity within 6 hours after AB leading to enhanced tumor necrosis factor-␣ (TNF␣) processing. In addition, TNF␣ production increased in timp-3 Ϫ/Ϫ-AB myocardium. A significant elevation in gelatinase and collagenase activities was observed 1 week after AB, with localized ECM degradation in timp-3 Ϫ/Ϫ-AB myocardium. Timp-3 Ϫ/Ϫ / tnf␣ Ϫ/Ϫ mice were generated and subjected to AB for comparative analyses with timp-3 Ϫ/Ϫ-AB mice. This revealed the critical role of TNF␣ in the early phase of LV remodeling, de novo expression of Matrix metalloproteinases (MMP)-8 in the absence of TNF␣, and highlighted the importance of interstitial collagenases (MMP-2, MMP-13, and MT1-MMP) for cardiac ECM degradation. Ablation of TNF␣, or limiting MMP activity with a synthetic MMP inhibitor (PD166793), each partially attenuated LV dilation and cardiac dysfunction in timp-3 Ϫ/Ϫ-AB mice. Notably, combining TNF␣ ablation with MMP inhibition completely rescued heart disease in timp-3 Ϫ/Ϫ-AB mice. This study provides a basis for anti-TNF␣ and MMP inhibitor combination therapy in heart disease.
2000
Cytokine and extracellular matrix (ECM) homeostasis are distinct systems that are each dysregulated in heart failure. Here we show that tissue inhibitor of metalloproteinase (TIMP)-3 is a critical regulator of both systems in a mouse model of left ventricular (LV) dilation and dysfunction. Timp-3 Ϫ/Ϫ mice develop precipitous LV dilation and dysfunction reminiscent of dilated cardiomyopathy (DCM), culminating in early onset of heart failure by 6 weeks, compared with wild-type aortic-banding (AB). Timp-3 deficiency resulted in increased TNF␣ converting enzyme (TACE) activity within 6 hours after AB leading to enhanced tumor necrosis factor-␣ (TNF␣) processing. In addition, TNF␣ production increased in timp-3 Ϫ/Ϫ -AB myocardium. A significant elevation in gelatinase and collagenase activities was observed 1 week after AB, with localized ECM degradation in timp-3 Ϫ/Ϫ -AB myocardium. Timp-3 Ϫ/Ϫ / tnf␣ Ϫ/Ϫ mice were generated and subjected to AB for comparative analyses with timp-3 Ϫ/Ϫ -AB mice. This revealed the critical role of TNF␣ in the early phase of LV remodeling, de novo expression of Matrix metalloproteinases (MMP)-8 in the absence of TNF␣, and highlighted the importance of interstitial collagenases (MMP-2, MMP-13, and MT1-MMP) for cardiac ECM degradation. Ablation of TNF␣, or limiting MMP activity with a synthetic MMP inhibitor (PD166793), each partially attenuated LV dilation and cardiac dysfunction in timp-3 Ϫ/Ϫ -AB mice. Notably, combining TNF␣ ablation with MMP inhibition completely rescued heart disease in timp-3 Ϫ/Ϫ -AB mice. This study provides a basis for anti-TNF␣ and MMP inhibitor combination therapy in heart disease. (Circ Res. 2005;97:380-390.) Key Words: left ventricular dilation and dysfunction Ⅲ extracellular matrix Ⅲ tissue inhibitor of metalloproteinase-3 Ⅲ matrix metalloproteinase Ⅲ tumor necrosis factor-␣
Circulation …, 2005
Cytokine and extracellular matrix (ECM) homeostasis are distinct systems that are each dysregulated in heart failure. Here we show that tissue inhibitor of metalloproteinase (TIMP)-3 is a critical regulator of both systems in a mouse model of left ventricular (LV) dilation and dysfunction. Timp-3 Ϫ/Ϫ mice develop precipitous LV dilation and dysfunction reminiscent of dilated cardiomyopathy (DCM), culminating in early onset of heart failure by 6 weeks, compared with wild-type aortic-banding (AB). Timp-3 deficiency resulted in increased TNF␣ converting enzyme (TACE) activity within 6 hours after AB leading to enhanced tumor necrosis factor-␣ (TNF␣) processing. In addition, TNF␣ production increased in timp-3 Ϫ/Ϫ-AB myocardium. A significant elevation in gelatinase and collagenase activities was observed 1 week after AB, with localized ECM degradation in timp-3 Ϫ/Ϫ-AB myocardium. Timp-3 Ϫ/Ϫ / tnf␣ Ϫ/Ϫ mice were generated and subjected to AB for comparative analyses with timp-3 Ϫ/Ϫ-AB mice. This revealed the critical role of TNF␣ in the early phase of LV remodeling, de novo expression of Matrix metalloproteinases (MMP)-8 in the absence of TNF␣, and highlighted the importance of interstitial collagenases (MMP-2, MMP-13, and MT1-MMP) for cardiac ECM degradation. Ablation of TNF␣, or limiting MMP activity with a synthetic MMP inhibitor (PD166793), each partially attenuated LV dilation and cardiac dysfunction in timp-3 Ϫ/Ϫ-AB mice. Notably, combining TNF␣ ablation with MMP inhibition completely rescued heart disease in timp-3 Ϫ/Ϫ-AB mice. This study provides a basis for anti-TNF␣ and MMP inhibitor combination therapy in heart disease.
Matrix Metalloproteinase 2 as a Pharmacological Target in Heart Failure
Pharmaceuticals
Heart failure (HF) is an acute or chronic clinical syndrome that results in a decrease in cardiac output and an increase in intracardiac pressure at rest or upon exertion. The pathophysiology of HF is heterogeneous and results from an initial harmful event in the heart that promotes neurohormonal changes such as autonomic dysfunction and activation of the renin-angiotensin-aldosterone system, endothelial dysfunction, and inflammation. Cardiac remodeling occurs, which is associated with degradation and disorganized synthesis of extracellular matrix (ECM) components that are controlled by ECM metalloproteinases (MMPs). MMP-2 is part of this group of proteases, which are classified as gelatinases and are constituents of the heart. MMP-2 is considered a biomarker of patients with HF with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF). The role of MMP-2 in the development of cardiac injury and dysfunction has clearly been demonstrated in animal models of cardiac...
Heart Failure Reviews, 2012
Chronic heart failure (CHF) is characterized by decreased nitric oxide (NO) bioavailability. In addition, the beneficial NO turns to be deleterious when it reacts with superoxide anion, leading to peroxynitrite formation. Numerous experimental and clinical studies have reported increased production of reactive oxygen species (superoxide, hydrogen peroxide, hydroxyl radical) both in animals and patients with CHF. Moreover, there are indicative data suggesting mechanisms associated with endothelial dysfunction in states of CHF, mainly attributed to decreased NO bioavailability and enhanced inactivation of the latter. Thus, such molecules appear to be potential targets in patients with CHF. These patients are strong candidates to receive a variety of therapeutic agents, some of which have known antioxidant effects. Classic treatment with statins or angiotensin converting enzyme inhibitors has been found to be beneficial in restoring NO and improving myocardial function and structure. Other agents such as sildenafil and b-blockers along with novel agents such as NO synthase transcription enhancers have been proved to be also beneficial, but their use for such a purpose is still controversial. Approaches using more-effective antioxidants or targeting myocardial oxidant-producing enzymes and oxidative or nitrosative stress might be promising strategies in the future.
Oxidative stress contributes to vascular endothelial dysfunction in heart failure
American Journal of Physiology-Heart and Circulatory Physiology, 2001
Congestive heart failure (HF) is characterized by inadequate nitric oxide (NO) production in the vasculature. Because NO is degraded by oxygen radicals, we hypothesized that NO is degraded faster in HF from inadequate peripheral arterial antioxidant reserves. HF was induced in male Sprague-Dawley rats by left coronary artery ligation. Vascular endothelial function was evaluated by measuring the NO-mediated vasorelaxation response to acetylcholine (ACh; 10−9–10−4 M) in excised aortas. This was repeated with the free radical generator pyrogallol (20 μM) and again with pyrogallol and superoxide dismutase (SOD; 60 U/ml). Aortic and myocardial SOD activity was also determined. ACh-induced vasorelaxation was reduced in HF ( n = 9) compared with normal control rats ( n = 11; P < 0.001). Pyrogallol further reduced vasorelaxation in HF: 74 ± 11% at 10−4 M ACh versus 58 ± 10% in normal control rats ( P < 0.004). There was a trend ( P = 0.06) toward reduced SOD activity in HF aortas. In ...