Myocardial lysyl oxidase regulation of cardiac remodeling in a murine model of diet-induced metabolic syndrome

Zibadi, Sherma; Vazquez, Randy; Moore, D.; Larson, Douglas F.; Watson, Ronald R.

doi:10.1152/ajpheart.00398.2009

Cited by 35 publications

(27 citation statements)

References 40 publications

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“…26) Furthermore, metabolic abnormalities produce enhanced fibrotic responses coincided with a marked increase in end-diastolic pressure, increased left ventricular stiffness, and impaired diastolic filling pattern in Otsuka Long-Evans Tokushima Fatty rats at insulin-resistant prediabetic stage 29) and a diet-induced metabolic syndrome murine model. 30) These findings and our data support the hypothesis that in metabolic syndrome, excess collagen formation in the myocardium was closely associated with ventricular diastolic dysfunction, eventually leading to diastolic heart failure. Recent observations found that matrix metalloproteinases (MMPs) contributed to the progression of chronic heart failure by regulating cardiac extracellular matrix metabolism; e.g.…”

Section: Discussionsupporting

confidence: 89%

Characterization of Cardiac Size and Function in SHRSP.Z-Leprfa/IzmDmcr Rats, a New Animal Model of Metabolic Syndrome

Tada

Kagota

Matsumoto

et al. 2010

Biological & Pharmaceutical Bulletin

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Lifestyle-related diseases-visceral obesity, hypertension, dyslipidemia and glucose intolerance-are known to appear in a cluster referred to as metabolic syndrome. As the number of disease components in metabolic syndrome increases in a patient, the structure and function of the heart becomes more compromised. 1) For example, metabolic syndrome increases the risk of atrial enlargement and fibrillation 2,3) and left ventricular hypertrophy and diastolic dysfunction. 1,4) These structural and functional abnormalities are considered to contribute to the increased cardiovascular morbidity and mortality associated with metabolic syndrome. However, the mechanisms underlying these abnormalities are not well understood.SHRSP.Z-Lepr fa /IzmDmcr rats (SHRSP-fatty) were established by crossing stroke-prone SHR (SHRSP/Izm) with Zucker obese rats to create a new animal model of metabolic syndrome.5) These rats develop spontaneous severe hypertension and obesity, and exhibit metabolic abnormalities (dyslipidemia, hyperinsulinemia and hyperglycemia), which are similar to those found in human metabolic syndrome. To date SHRSP-fatty have been used in studies that evaluated dysfunction of vasodilation mechanisms, cardiovascular remodeling, and atherogenic dyslipidemia in metabolic syndrome. [6][7][8] The aim of the present study was to characterize the cardiac structure and function in SHRSP-fatty. Increased cardiac stiffness induced by disturbed myocardial collagen turnover is suggested as one of the mechanisms of cardiac abnormalities in hypertension and diabetes.9,10) Therefore, as structural parameters, heart weight and a major myocardial collagen, collagen type I, as an index of fibrosis, were measured. Additionally, collagen type III, which contributes to tissue elasticity, was measured and the ratio of type I to type III was calculated as an index of myocardial stiffness. To assess cardiac function in SHRSP-fatty, heart rate, systolic blood pressure, cardiac output, blood flow and stroke volume were measured by tail-cuff and plethysmography, and compared to those in hypertensive lean SHRSP and normotensive lean WistarKyoto rats (WKY). Systolic and diastolic cardiac functions were also determined by echocardiography. The results may inform us whether this model would be a useful animal model to evaluate cardiac complications of metabolic syndrome. MATERIALS AND METHODS Experimental AnimalsMale SHRSP-fatty (nϭ18), SHRSP (nϭ18) and normotensive control WKY (nϭ18) were purchased at 16 weeks of age from Japan SLC, Inc. (Hamamatsu, Japan). The rats were established by the Disease Model Cooperative Research Association (Hamamatsu, Japan). Standard chow (CE-2; Clea Japan Inc., Tokyo, Japan) and water were available ad libitum during the experimental period. The study protocols were performed according to the Guideline for the Care and Use of Laboratory Animals approved by Mukogawa Women's University.Tail-Cuff Method and Plethysmography Systolic blood pressure and heart rate of conscious rats were meas- Cardiac structural and funct...

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Section: Discussionsupporting

confidence: 89%

Characterization of Cardiac Size and Function in SHRSP.Z-Leprfa/IzmDmcr Rats, a New Animal Model of Metabolic Syndrome

Tada

Kagota

Matsumoto

et al. 2010

Biological & Pharmaceutical Bulletin

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“…5 In 2006, we reported that LOXL-1 mRNA was upregulated in pressure overloaded hypertrophied hearts induced by abdominal aortic constriction (AAC). 6 Since then, similar findings have been reported in animal models of diet-induced fibrotic hearts, cardiac remodeling of diet-induced metabolic syndrome and hypertrophied hearts of spontaneously hypertensive rats, [7][8][9] as well as in patients with dilated cardiomyopathy and heart failure. 10,11 These studies found upregulation of both mRNA and protein levels of LOX family in the remodeled hearts, and these expression levels were correlated with the degree of cardiac fibrosis, indicating that LOX and LOXLs have a role in cardiac remodeling by inducing fibrosis.…”

Section: Introductionsupporting

confidence: 61%

Cardiomyocyte-specific transgenic expression of lysyl oxidase-like protein-1 induces cardiac hypertrophy in mice

et al. 2012

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Lysyl oxidase (LOX) and LOX-like protein-1 (LOXL-1) are extracellular matrix-embedded amine oxidases that have critical roles in the cross-linking of collagen and elastin. LOX family proteins are abundantly expressed in the remodeled heart of animals and humans and are implicated in cardiac fibrosis; however, their role in cardiac hypertrophy is unknown. In this study, in vitro stimulation with hypertrophic agonists significantly increased LOXL-1 expression, LOX enzyme activity and [ 3 H] leucine incorporation in neonatal rat cardiomyocytes. A LOX inhibitor, beta-aminopropionitrile (BAPN), inhibited agonist-induced leucine incorporation in cardiomyocytes in vitro, suggesting the involvement of LOXL-1 in cardiomyocyte hypertrophy. Abdominal aortic constriction in rats produced left ventricular hypertrophy in parallel with LOXL-1 mRNA upregulation. And BAPN administration significantly inhibited angiotensin II-induced cardiac hypertrophy in vivo. These results suggest a role of LOXL-1 in cardiac hypertrophy in vivo. We generated transgenic mice with cardiomyocyte-specific expression of LOXL-1. LOXL-1 transgenic mice pups were born normally and grew to adulthood without increased mortality; these mice exhibited a greater left ventricle to body weight ratio, larger myocyte diameter, and more brain natriuretic peptide expression than their wild-type littermates. Echocardiography revealed that the LOXL-1 transgenic mice also had greater wall thickness with preserved cardiac contraction. Our results indicate a possible fundamental role of LOXL-1 in cardiac hypertrophy.

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“…This fibrotic response coincided with a marked increase in end-diastolic pressure, increased LV stiffness, and an impaired diastolic filling pattern (82). Therefore, LOX may be involved in the pathophysiology of metabolic syndrome-associated myocardial remodeling that underlies alterations of the LV mechanical properties and function in this syndrome.…”

Section: Role Of Lox In Myocardial Fibrosismentioning

confidence: 93%

“…In the LV myocardium of C57BL/6 mice with metabolic syndrome induced by administrating a high-fat, high-simple carbohydrate diet for 6 mo, there was an increase in the ratio of mature to proenzyme LOX, enhanced LOX activity, increased cross-linked collagen, and interstitial fibrotic tissue compared with the controls (82). This fibrotic response coincided with a marked increase in end-diastolic pressure, increased LV stiffness, and an impaired diastolic filling pattern (82).…”

Section: Role Of Lox In Myocardial Fibrosismentioning

confidence: 97%

Role of lysyl oxidase in myocardial fibrosis: from basic science to clinical aspects

López

González

Hermida

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

220

198

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Because of its dynamic nature, the composition and structure of the myocardial collagen network can be reversibly modified to adapt to transient cardiac injuries. In response to persistent injury, however, irreversible, maladaptive changes of the network occur leading to fibrosis, mostly characterized by the excessive interstitial and perivascular deposition of collagen types I and III fibers. It is now becoming apparent that myocardial fibrosis directly contributes to adverse myocardial remodeling and the resulting alterations of left ventricular (LV) anatomy and function present in the major types of cardiac diseases. The enzyme lysyl oxidase (LOX) is a copper-dependent extracellular enzyme that catalyzes lysine-derived cross-links in collagen and elastin. LOXmediated cross-linking of collagen types I and III fibrils leads to the formation of stiff collagen types I and III fibers and their subsequent tissue deposition. Evidence from experimental and clinical studies shows that the excess of LOX is associated with an increased collagen cross-linking and stiffness. It is thus conceivable that LOX upregulation and/or overactivity could underlie myocardial fibrosis and altered LV mechanics and contribute to the compromise of LV function in cardiac diseases. This review will consider the molecular aspects related to the regulation and actions of LOX, namely, in the context of collagen synthesis. In addition, it will address the information related to the role of myocardial LOX in heart failure and the potential benefits of controlling its expression and function. collagen; diastolic dysfunction; hypertensive heart disease; myocardial remodeling THE ELEVATION IN myocardial stress that results from cardiac injury and/or persistent elevations in ventricular pressure or volume triggers a response of the myocardium in an attempt to return the tissue stress to its normal value. This response leads to progressive structural remodeling of the cardiomyocyte, vascular and extracellular matrix (ECM) components of the myocardium that manifest as changes in ventricular wall and chamber dimensions, as well as in diastolic and systolic function (5).Alterations in the myocardial collagen network are a hallmark of the ECM response to stress, either hemodynamic or nonhemodynamic in origin. A collagen network, composed largely of collagen types I and III fibers, is found in the interstitial space of the myocardium. Because collagen is a relatively stiff material with a high-tensile strength, small changes in its concentration have been shown to exert marked effects on the passive mechanical properties of the human heart (7). In addition to the concentration of collagen, experimental data suggest that the passive behavior of the myocardium may also be dependent on the relative proportion of the types of collagen, the diameter of the collagen fibers and their spatial alignment, and the degree of cross-linking. Accordingly, tissue containing predominantly type I collagen, large-diameter collagen fibers, and/or a high degree of cross-lin...

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Myocardial lysyl oxidase regulation of cardiac remodeling in a murine model of diet-induced metabolic syndrome

Cited by 35 publications

References 40 publications

Characterization of Cardiac Size and Function in SHRSP.Z-Leprfa/IzmDmcr Rats, a New Animal Model of Metabolic Syndrome

Characterization of Cardiac Size and Function in SHRSP.Z-Leprfa/IzmDmcr Rats, a New Animal Model of Metabolic Syndrome

Cardiomyocyte-specific transgenic expression of lysyl oxidase-like protein-1 induces cardiac hypertrophy in mice

Role of lysyl oxidase in myocardial fibrosis: from basic science to clinical aspects

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