Integrins and proximal signaling mechanisms in cardiovascular disease

Lal, Hind; Verma, Suresh; Foster, Donald M.; Golden, Honey B.; Reneau, John; Watson, Linley E.; Singh, Harbans; Dostal, David E.

doi:10.2741/3381

Cited by 74 publications

(70 citation statements)

References 261 publications

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“…The Fbn1 mgR/mgR mouse model demonstrates severe mitral and aortic regurgitation with LV dilatation. This mechanical stretch imposed on the LV can induce the AT1R in a ligand-independent manner leading to cardiomyocyte hypertrophy (16,40). In accordance with these findings, cardiomyocyte hypertrophy was evidenced in the Fbn1 mgR/mgR mouse model (11).…”

Section: Discussionmentioning

confidence: 99%

“…To this aim, we performed western blotting of β1, α5, and α9 integrin. β1 integrin is the primary β integrin subunit expressed in the myocardium and has previously been linked to the development of dilated CMP (16)(17)(18) and α5 and α9 integrin directly bind to fibrillin-1 ((23,24), personal communication, Prof. L. Sakai). β1, α5, and α9 integrins were not differentially expressed (P = 0.73-0.91) ( Figure 5).…”

Section: Canonical and Noncanonical Tgfβ Signaling Is Upregulated In mentioning

confidence: 99%

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Intrinsic cardiomyopathy in Marfan syndrome: results from in-vivo and ex-vivo studies of the Fbn1C1039G/+ model and longitudinal findings in humans

et al. 2015

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Background: Mild intrinsic cardiomyopathy in patients with Marfan syndrome (MFS) has consistently been evidenced by independent research groups. So far, little is known about the long-term evolution and pathophysiology of this finding. Methods: To gain more insights into the pathophysiology of MFS-related cardiomyopathy, we performed in-vivo and ex-vivo studies of 11 Fbn1 C1039G/+ mice and 9 wild-type (WT) littermates. Serial ultrasound findings obtained in mice were correlated to the human phenotype. We therefore reassessed left ventricular (LV) function parameters over a 6-y follow-up period in 19 previously reported MFS patients, in whom we documented mild LV dysfunction. results: Fbn1C1039G/+ mice demonstrated LV contractile dysfunction. Subsequent ex-vivo studies of the myocardium of adult mutant mice revealed upregulation of TGFβ-related pathways and consistent abnormalities of the microfibrillar network, implicating a role for microfibrils in the mechanical properties of the myocardium. Echocardiographic parameters did not indicate clinical significant deterioration of LV function during follow-up in our patient cohort. conclusion: In analogy with what is observed in the majority of MFS patients, the Fbn1 C1039G/+ mouse model demonstrates mild intrinsic LV dysfunction. Both extracellular matrix and molecular alterations are implicated in MFS-related cardiomyopathy. This model may now enable us to study therapeutic interventions on the myocardium in MFS. M arfan syndrome (MFS, GenBank accession nos. L13923)is an autosomal dominant inherited connective tissue disorder caused by mutations in the fibrillin-1 gene (FBN1) encoding the extracellular matrix protein fibrillin-1. The clinical diagnosis of MFS relies on the identification of characteristic clinical manifestations, mainly occurring in the cardiovascular, musculoskeletal, and ocular system, as summarized in the ''Revised Ghent Nosology'' , and may be supplemented by the identification of a causal FBN1 mutation (1).Cardiovascular involvement in MFS is characterized by progressive dilatation of the ascending aorta at the level of the sinuses of Valsalva, ensuing a risk for type A aortic dissection or -rupture and aortic valve regurgitation (2). Other established cardiovascular manifestations of MFS include mitral valve prolapse and pulmonary artery dilatation. More recently, several independent studies demonstrated the presence ofmostly subclinical-intrinsic cardiomyopathy (CMP) with both left and right ventricular (LV and RV) systolic and diastolic dysfunction in MFS patients (3,4). The current knowledge of MFS-related CMP is based on cross-sectional studies, but little is known about the long-term evolution and pathophysiology of this finding.To unravel the underlying pathophysiology of MFS-related CMP, the knowledge obtained from the study of other MFS manifestations may at least be partly translated to the cardiac phenotype. Upregulation of TGFβ signaling, with activation of the canonical (SMAD2/3) and noncanonical (predominantly ERK1/2) pathways, i...

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Section: Discussionmentioning

confidence: 99%

Section: Canonical and Noncanonical Tgfβ Signaling Is Upregulated In mentioning

confidence: 99%

Intrinsic cardiomyopathy in Marfan syndrome: results from in-vivo and ex-vivo studies of the Fbn1C1039G/+ model and longitudinal findings in humans

et al. 2015

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“…Together, these results corroborate our hypothesis that persistent mechanical stress causes spontaneous DCM in MFS mice. Integrins are a class of cardiac mechanosensors that interact with the ECM to convert hemodynamic load into biochemical signals, such as FAK phosphorylation (48). We interpreted the barely detectable amounts of pFAK in the LV of 3-month-old Fbn1 mgR/mgR mice as additional evidence that fibrillin 1 deficiency interferes with cardiac cell mechanosensing ( Figure 5A).…”

Section: Dcm Is Part Of the Cardiovascular Phenotype Of Mice With Sevmentioning

confidence: 99%

Abnormal muscle mechanosignaling triggers cardiomyopathy in mice with Marfan syndrome

Cook¹,

Carta²,

Bénard³

et al. 2014

J. Clin. Invest.

121

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Patients with Marfan syndrome (MFS), a multisystem disorder caused by mutations in the gene encoding the extracellular matrix (ECM) protein fibrillin 1, are unusually vulnerable to stress-induced cardiac dysfunction. The prevailing view is that MFS-associated cardiac dysfunction is the result of aortic and/or valvular disease. Here, we determined that dilated cardiomyopathy (DCM) in fibrillin 1-deficient mice is a primary manifestation resulting from ECM-induced abnormal mechanosignaling by cardiomyocytes. MFS mice displayed spontaneous emergence of an enlarged and dysfunctional heart, altered physical properties of myocardial tissue, and biochemical evidence of chronic mechanical stress, including increased angiotensin II type I receptor (AT1R) signaling and abated focal adhesion kinase (FAK) activity. Partial fibrillin 1 gene inactivation in cardiomyocytes was sufficient to precipitate DCM in otherwise phenotypically normal mice. Consistent with abnormal mechanosignaling, normal cardiac size and function were restored in MFS mice treated with an AT1R antagonist and in MFS mice lacking AT1R or β-arrestin 2, but not in MFS mice treated with an angiotensin-converting enzyme inhibitor or lacking angiotensinogen. Conversely, DCM associated with abnormal AT1R and FAK signaling was the sole abnormality in mice that were haploinsufficient for both fibrillin 1 and β1 integrin. Collectively, these findings implicate fibrillin 1 in the physiological adaptation of cardiac muscle to elevated workload.

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“…Integrins act as biomechanical sensors and convert mechanical stress, to biochemical signals. 35,36 One of the well-known intracellular signaling pathways activated by integrin ␤1 is phosphorylation of focal adhesion kinase (FAK). [37][38][39] Consistent with reduced integrin ␤1 levels in the TIMP2 Ϫ/Ϫ -TAC cardiomyocyte membranes, p-FAK levels were significantly lower in these hearts compared with WT-TAC hearts ( Figure 6D).…”

Section: -Tac Heartsmentioning

confidence: 99%

Lack of Tissue Inhibitor of Metalloproteinases 2 Leads to Exacerbated Left Ventricular Dysfunction and Adverse Extracellular Matrix Remodeling in Response to Biomechanical Stress

et al. 2011

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Background-Remodeling of the extracellular matrix (ECM) is a key aspect of myocardial response to biomechanical stress and heart failure. Tissue inhibitors of metalloproteinases (TIMPs) regulate the ECM turnover through negative regulation of matrix metalloproteinases (MMPs), which degrade the ECM structural proteins. Tissue inhibitor of metalloproteinases 2 is unique among TIMPs in activating pro-MMP2 in addition to inhibiting a number of MMPs. Given this dual role of TIMP2, we investigated whether TIMP2 serves a critical role in heart disease. Methods and Results-Pressure overload by transverse aortic constriction (TAC) in 8-week-old male mice resulted in greater left ventricular hypertrophy, fibrosis, dilation, and dysfunction in TIMP2-deficient (TIMP2) compared with wild-type mice at 2 weeks and 5 weeks post-TAC. Despite lack of MMP2 activation, total collagenase activity and specific membrane type MMP activity were greater in TIMP2 Ϫ/Ϫ -TAC hearts. Loss of TIMP2 resulted in a marked reduction of integrin ␤1D levels and compromised focal adhesion kinase phosphorylation, resulting in impaired adhesion of cardiomyocytes to ECM proteins, laminin, and fibronectin. Nonuniform ECM remodeling in TIMP2 Ϫ/Ϫ -TAC hearts revealed degraded network structure as well as excess fibrillar deposition. Greater fibrosis in TIMP2 Ϫ/Ϫ -TAC compared with wild-type TAC hearts was due to higher levels of SPARC (secreted protein acidic and rich in cysteine) and posttranslational stabilization of collagen fibers rather than increased collagen synthesis. Inhibition of MMPs including membrane type MMP significantly reduced left ventricular dilation and dysfunction, hypertrophy, and fibrosis in TIMP2 Key Words: tissue inhibitor of metalloproteinases Ⅲ membrane-type matrix metalloproteinases Ⅲ fibrosis Ⅲ hypertrophy I ncreased afterload leading to excess biomechanical stress is a common cause of left ventricular (LV) remodeling, which leads to cardiac dysfunction and eventual heart failure. 1,2 The extracellular matrix (ECM) is a dynamic structure, and its turnover is a physiological process that takes place in all organs. Adverse remodeling of the myocardial ECM, brought about by dysregulation in its turnover, is a key component of pressure overload-induced cardiomyopathy. This results in excess degradation and disruption of the ECM network structure or accumulation of ECM proteins and formation of fibrotic lesions. Myocardial fibrosis is also a well-known cause of diastolic dysfunction and diastolic heart failure. [3][4][5][6][7] Matrix metalloproteinases (MMPs) degrade ECM proteins, whereas their proteolytic activity is kept in check by their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMPs). An imbalance in the function of MMPs and TIMPs occurs in heart disease, leading to adverse ECM remodeling, and TIMPs are emerging as critical regulators of this process. 8 -13 Editorial see p 2052 Clinical Perspective on p 2105Among the 4 TIMPs, 14 TIMP2 has the unique property of activating MMP2 through formation of a tr...

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Integrins and proximal signaling mechanisms in cardiovascular disease

Cited by 74 publications

References 261 publications

Intrinsic cardiomyopathy in Marfan syndrome: results from in-vivo and ex-vivo studies of the Fbn1C1039G/+ model and longitudinal findings in humans

Intrinsic cardiomyopathy in Marfan syndrome: results from in-vivo and ex-vivo studies of the Fbn1C1039G/+ model and longitudinal findings in humans

Abnormal muscle mechanosignaling triggers cardiomyopathy in mice with Marfan syndrome

Lack of Tissue Inhibitor of Metalloproteinases 2 Leads to Exacerbated Left Ventricular Dysfunction and Adverse Extracellular Matrix Remodeling in Response to Biomechanical Stress

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