Abstract
Arrhythmogenic cardiomyopathy (AC) is an incurable genetic disease, whose pathogenesis is poorly understood. AC is characterized by arrhythmia, fibrosis, and cardiodilation that may lead to sudden cardiac death or heart failure. To elucidate AC pathogenesis and to design possible treatment strategies of AC, multiple murine models have been established. Among them, mice carrying desmoglein 2 mutations are particularly valuable given the identification of desmoglein 2 mutations in human AC and the detection of desmoglein 2 auto-antibodies in AC patients. Using two mouse strains producing either a mutant desmoglein 2 or lacking desmoglein 2 in cardiomyocytes, we test the hypothesis that inflammation is a major component of disease pathogenesis. We show that multifocal cardiomyocyte necrosis initiates a neutrophil-dominated inflammatory response, which also involves macrophages and T cells. Increased expression of Ccl2/Ccr2, Ccl3/Ccr5, and Cxcl5/Cxcr2 mRNA reflects the observed immune cell recruitment. During the ensuing acute disease phase, Mmp12+ and Spp1+ macrophages and T cells accumulate in scars, which mature from cell- to collagen-rich. The expression of Cx3cl1/Cx3cr1, Ccl2/Ccr2, and Cxcl10/Cxcr3 dominates this disease phase. We furthermore find that during chronic disease progression macrophages and T cells persist within mature scars and are present in expanding interstitial fibrosis. Ccl12 and Cx3cl1 are predominant chemokines in this disease phase. Together, our observations provide strong evidence that specific immune cell populations and chemokine expression profiles modulate inflammatory and repair processes throughout AC progression.
Highlights
Arrhythmogenic cardiomyopathy (AC), previously referred to as arrhythmogenic right ventricular cardiomyopathy (ARVC), is a genetic disease that is characterized by arrhythmia and cardiac dilation
It has been suggested that cardiomyocyte necrosis is the key pathogenic event triggering an inflammatory response in murine Dsg2-related AC [40, 53]
We studied the mRNA expression of osteopontin (Spp1), which is a marker for reparative macrophages [49, 55, 57], the matrix metalloproteinase 12, a macrophage-specific elastase expressed in pro-inflammatory macrophages [4], and the lectin YM1 (CHI3L3), which is an indicator for reparative or alternatively activated macrophages [45]
Summary
Arrhythmogenic cardiomyopathy (AC), previously referred to as arrhythmogenic right ventricular cardiomyopathy (ARVC), is a genetic disease that is characterized by arrhythmia and cardiac dilation. Several mouse strains have been described that either overexpress mutant desmoglein 2 protein (denoted as DSG2) [52], lack DSG2 in cardiomyocytes [38] or constitutively produce mutant DSG2 [14, 42] reflecting situations encountered in human AC patients ranging between homo- and heterozygosity and between mutant and absent DSG2 [17, 18, 58]. Morphological disease onset with localized lesion formation was observed 2 weeks after birth It is followed by the acute disease phase during which lesions are transformed into mature fibrous scars by the age of 10–12 weeks. The chronic disease phase sets in with progressive cardiac wall alterations in aging mice [31, 40]
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