chondroitin-sulfates and Cardiomyopathies

Heart failure is a leading cause of mortality and morbidity, and the search for novel therapeutic approaches continues. In the monogenic disease mucopolysaccharidosis VI, loss-of-function mutations in arylsulfatase B lead to myocardial accumulation of chondroitin sulfate (CS) glycosaminoglycans, manifesting as myriad cardiac symptoms. Here, we studied changes in myocardial CS in nonmucopolysaccharidosis failing hearts and assessed its generic role in pathological cardiac remodeling.. Healthy and diseased human and rat left ventricles were subjected to histological and immunostaining methods to analyze glycosaminoglycan distribution. Glycosaminoglycans were extracted and analyzed for quantitative and compositional changes with Alcian blue assay and liquid chromatography-mass spectrometry. Expression changes in 20 CS-related genes were studied in 3 primary human cardiac cell types and THP-1-derived macrophages under each of 9 in vitro stimulatory conditions. In 2 rat models of pathological remodeling induced by transverse aortic constriction or isoprenaline infusion, recombinant human arylsulfatase B (rhASB), clinically used as enzyme replacement therapy in mucopolysaccharidosis VI, was administered intravenously for 7 or 5 weeks, respectively. Cardiac function, myocardial fibrosis, and inflammation were assessed by echocardiography and histology. CS-interacting molecules were assessed with surface plasmon resonance, and a mechanism of action was verified in vitro.. Failing human hearts displayed significant perivascular and interstitial CS accumulation, particularly in regions of intense fibrosis. Relative composition of CS disaccharides remained unchanged. Transforming growth factor-β induced CS upregulation in cardiac fibroblasts. CS accumulation was also observed in both the pressure-overload and the isoprenaline models of pathological remodeling in rats. Early treatment with rhASB in the transverse aortic constriction model and delayed treatment in the isoprenaline model proved rhASB to be effective at preventing cardiac deterioration and augmenting functional recovery. Functional improvement was accompanied by reduced myocardial inflammation and overall fibrosis. Tumor necrosis factor-α was identified as a direct binding partner of CS glycosaminoglycan chains, and rhASB reduced tumor necrosis factor-α-induced inflammatory gene activation in vitro in endothelial cells and macrophages.. CS glycosaminoglycans accumulate during cardiac pathological remodeling and mediate myocardial inflammation and fibrosis. rhASB targets CS effectively as a novel therapeutic approach for the treatment of heart failure.

Topics: Animals; Cardiomyopathies; Chondroitin Sulfates; Fibrosis; Heart Failure; Heart Ventricles; Humans; Mice; Myocardium; Rats; Ventricular Remodeling

Patterns of amyloid distribution and extracellular matrix changes in the heart and gastrointestinal tract were compared among beta 2-microglobulin (B2M), AA (secondary), and AL (primary and multiple myeloma-associated) amyloidosis cases. B2M amyloid was found to be mainly distributed in the small arterioles, venules, endocardium and muscularis propria of these organs, the deposits characteristically forming subendothelial nodular lesions in the vessels. A marked increase of chondroitin sulfate (CS) was consistently detected in B2M amyloid. Heparan sulfate (HS) also showed an increase in amyloid deposits, but with less reactivity than CS in the small arterioles or venules. Basement membrane structures stained positively for laminin and collagen type IV were replaced by negative amyloid deposits. In the AL cases, the muscularis propria of the gastrointestinal tract was involved in amyloid deposits, as seen for the B2M type, but the vascular amyloid deposits were localized in the media and adventitia of larger vessels. Immunoreactivity for HS was more intense than that for CS, and no increase in laminin or collagen type IV was observed. In the AA cases, amyloid deposits were distributed in the capillaries, small arterioles, interstitium of the myocardium and mucosa. Immunoreactivity for laminin and collagen type IV was marked, and more intense than that for HS and CS. Although the existence of a direct relationship between increase in extracellular matrix material and amyloidogenesis remains to be proven, the observed variation in extracellular matrix changes in the background of each type of amyloidosis may indicate different binding sites of the amyloid precursor proteins, resulting in the specific histological features and distribution.

Topics: Adult; Aged; Aged, 80 and over; Amyloid; Amyloid beta-Protein Precursor; Amyloidosis; beta 2-Microglobulin; Cardiomyopathies; Chondroitin Sulfates; Digestive System; Extracellular Matrix; Female; Gastrointestinal Diseases; Heparitin Sulfate; Humans; Male; Middle Aged; Myocardium; Renal Dialysis

The myocardial extracellular matrix (ECM) is composed of three important constituents: (1) fibrillar collagen, (2) a basement membrane, and (3) proteoglycans. Structural or compositional changes in these ECM components may affect left ventricular (LV) function as well as influence overall LV geometry. Accordingly, this study examined the relationship between changes in these ECM components to changes in LV function and geometry which develop with the progression and regression from supraventricular tachycardia-induced cardiomyopathy (SVT). LV function and specific components of the ECM were studied in pigs with SVT cardiomyopathy (SVT:atrially paced 240 bpm, 3 weeks; n = 7), or after a 4-week recovery from SVT cardiomyopathy (post-SVT; n = 6), and in controls (n = 7). LV fractional shortening fell by 60% and end-diastolic dimension increased by 47% with SVT compared to controls. While LV fractional shortening normalized with post-SVT, end-diastolic dimension remained 40% higher than controls. Collagen concentration fell by 22% and salt extractable collagen, which reflects collagen cross-linking, increased by 41% with SVT compared to controls. Collagen concentration increased by 20%, collagen extraction normalized, and levels of collagen type III mRNA increased by 42% with post-SVT. Isolated myocyte adhesion capacity to basement membrane substrates laminin, fibronectin, and collagen type IV were examined. SVT resulted in over a 50% reduction in myocyte adhesion for all of the basement membrane components compared to controls. A normalization in isolated myocyte adhesion capacity was observed in post-SVT. The relative content and distribution of the ECM proteoglycan chondroitin sulfate was examined using immunohistochemistry. With SVT, the density of this proteoglycan increased around individual myocytes. With post-SVT, the relative distribution of chondroitin sulfate returned to control levels. Thus, SVT cardiomyopathy was associated with reduced collagen concentration and cross-linking, diminished myocyte basement membrane adhesion capacity, and increased proteoglycans. Recovery from SVT cardiomyopathy resulted in increased collagen concentration, and a normalization of myocyte adhesion capacity and proteoglycan distribution. These results suggest that changes within the ECM are a dynamic process and accompany the LV systolic and diastolic function as well as ventricular and myocyte remodeling during the progression and regression from cardiomyopathic dis

Topics: Analysis of Variance; Animals; Basement Membrane; Cardiomyopathies; Cell Adhesion; Chondroitin Sulfates; Collagen; Extracellular Matrix; Heart Rate; Macromolecular Substances; Myofibrils; Proteoglycans; RNA, Messenger; Swine; Ventricular Function, Left