Disruption of Collagen Homeostasis Can Reverse Established Age-Related Myocardial Fibrosis

Abstract

Heart failure, the leading cause of hospitalization of elderly patients, is correlated with myocardial fibrosis (ie, deposition of excess extracellular matrix proteins such as collagen). A key regulator of collagen homeostasis is lysyl oxidase (LOX), an enzyme responsible for cross-linking collagen fibers. Our objective was to ameliorate age-related myocardial fibrosis by disrupting collagen cross-linking through inhibition of LOX. The nonreversible LOX inhibitor β-aminopropionitrile (BAPN) was administered by osmotic minipump to 38-week-old C57BL/6J male mice for 2 weeks. Sirius Red staining of myocardial cross sections revealed a reduction in fibrosis, compared with age-matched controls (5.84 ± 0.30% versus 10.17 ± 1.34%) (P < 0.05), to a level similar to that of young mice at 8 weeks (4.9 ± 1.2%). BAPN significantly reduced COL1A1 mRNA, compared with age-matched mice (3.5 ± 0.3-fold versus 15.2 ± 4.9-fold) (P < 0.05), suggesting that LOX is involved in regulation of collagen synthesis. In accord, fibrotic factor mRNA expression was reduced after BAPN. There was also a novel increase in Ly6C expression by resident macrophages. By interrupting collagen cross-linking by LOX, the BAPN treatment reduced myocardial fibrosis. A novel observation is that BAPN treatment modulated the transforming growth factor-β pathway, collagen synthesis, and the resident macrophage population. This is especially valuable in terms of potential therapeutic targeting of collagen regulation and thereby age-related myocardial fibrosis.

Cardiac Function Remains Impaired Despite Reversible Cardiac Remodeling after Acute Experimental Viral Myocarditis

“…Gene expression analysis revealed that Timp1 expression was decreased to basal level resulting in normal MMP activity. We assume that the newly synthesized collagen was not appropriately cross-linked since this postsynthetic collagen processing makes collagen less prone to degradation by collagenases [53]. A regression of cardiac fibrosis is already reported in lisinopril-treated hypertensive patients and hypertensive rats [54, 55].…”

The Role of Lysyl Oxidase Enzymes in Cardiac Function and Remodeling

“…In this scenario, disrupting CCL through inhibition of LOX is expected to reverse fibrosis and ameliorate cardiac dysfunction. Indeed, the administration of β-aminopropionitrile (BAPN), an irreversible LOX inhibitor, to 38-week-old mice reversed established age-related myocardial fibrosis to a level similar to that of young mice [58]. The inhibition of LOX by BAPN modulated TGF-β signaling and collagen synthesis, but also the degree of macrophage infiltration [58].…”

“…Indeed, the administration of β-aminopropionitrile (BAPN), an irreversible LOX inhibitor, to 38-week-old mice reversed established age-related myocardial fibrosis to a level similar to that of young mice [58]. The inhibition of LOX by BAPN modulated TGF-β signaling and collagen synthesis, but also the degree of macrophage infiltration [58]. In the rat model of aortocaval fistula-induced volume overload (VO), the expression and activity of LOX, as well as collagen and CCL, were progressively upregulated in parallel with an enhanced ventricular mass [59].…”

Mechanisms of Lung Fibrosis Resolution

“…Recent studies demonstrate that inhibition of lysyl oxidaseelike-2 experimentally reduced myocardial fibrosis and also prevented and reversed bleomycin-induced lung fibrosis. 32,33 Thus, although manipulating extracellular proteases may be premature because of the limited understanding of their precise function in ECM turnover, targeting pathways that allow better access of extracellular proteases to the ECM is promising. Monoclonal antibodies to lysyl oxidasee like-2 have been tested in phase 2 trials in IPF, and smallmolecule lysyl oxidaseelike-2 selective inhibitors have been developed and are expected to enter phase 1 trials for the treatment of pulmonary fibrotic disease.…”