Deletion of Microfibrillar‐Associated Protein 4 Attenuates Left Ventricular Remodeling and Dysfunction in Heart Failure

Abstract

Background Cardiac remodeling predisposes individuals to heart failure if the burden is not solved, and heart failure is a growing cause of morbidity and mortality worldwide. The cardiac extracellular matrix not only provides structural support, but also is a core aspect of the myocardial response to various biomechanical stresses and heart failure. MFAP4 (microfibrillar‐associated protein 4) is an integrin ligand located in the extracellular matrix, whose biological functions in the heart remain poorly understood. In the current study we aimed to test the role of MFAP4 in cardiac remodeling. Methods and Results MFAP4‐deficient (MFAP4 −/− ) and wild‐type mice were subjected to aortic banding surgery and isoproterenol to establish models of cardiac remodeling. We also evaluated the functional effects of MFAP4 on cardiac hypertrophy, fibrosis, and cardiac electrical remodeling. The expression of MFAP4 was increased in the animal cardiac remodeling models induced by pressure overload and isoproterenol. After challenge of 8 weeks of aortic banding or 2 weeks of intraperitoneal isoproterenol, MFAP4 −/− mice exhibited lower levels of cardiac fibrosis and fewer ventricular arrhythmias than wild‐type mice. However, there was no significant effect on cardiomyocyte hypertrophy. In addition, there was no significant difference in cardiac fibrosis severity, hypertrophy, or ventricular arrhythmia incidence between wild‐type‐sham and knockout‐sham mice. Conclusions These findings are the first to demonstrate that MFAP4 deficiency inhibits cardiac fibrosis and ventricular arrhythmias after challenge with 8 weeks of aortic banding or 2 weeks of intraperitoneal isoproterenol but does not significantly affect the hypertrophy response. In addition, MFAP4 deficiency had no significant effect on cardiac fibrosis, hypertrophy, or ventricular arrhythmia in the sham group in this study.

Identification of candidate biomarkers and therapeutic agents for heart failure by bioinformatics analysis

“…Experiments show that expression of FAP (fibroblast activation protein alpha) [ 75 ], THBS4 [ 76 ], CD27 [ 77 ], LEF1 [ 78 ], CTHRC1 [ 79 ], ESR1 [ 80 ], CXCL9 [ 81 ], SERPINA3 [ 82 ], TRPC4 [ 83 ], F13A1 [ 84 ], PIK3C2A [ 85 ], KCNIP2 [ 86 ] and GPR4 [ 87 ] contributed to myocardial infarction. MFAP4 [ 88 ], ALOX15 [ 89 ], COL1A1 [ 90 ], APOA1 [ 91 ], PDE5A [ 92 ], CX3CR1 [ 93 ], THY1 [ 94 ], GREM1 [ 95 ], FMOD (fibromodulin) [ 96 ], NPPA (natriuretic peptide A) [ 97 ], LTBP2 [ 98 ], LUM (lumican) [ 99 ], IL34 [ 100 ], NRG1 [ 101 ], CXCL14 [ 102 ], CXCL10 [ 103 ], ACE (angiotensin I converting enzyme) [ 104 ], CFTR (ystic fibrosis transmembrane conductance regulator) [ 105 ], S100A8 [ 106 ], S100A9 [ 106 ], HP (haptoglobin) [ 107 ], AGTR1 [ 108 ], ATP2A2 [ 109 ], IL10 [ 110 ], EDN1 [ 111 ], TLR2 [ 112 ], MCEMP1 [ 113 ], TPO (thyroid peroxidase) [ 114 ], CD163 [ 115 ], IL18R1 [ 116 ], KCNA7 [ 117 ] and CALCRL (calcitonin receptor like receptor) [ 118 ] have an important role in HF. Li et al [ 119 ], Deckx et al [ 120 ], Ichihara et al [ 121 ] and Paik et al [ 122 ] showed that the SERPINE2, OGN (osteoglycin), AGTR2 and WNT10B promoted cardiac interstitial fibrosis.…”

Dissecting the Cellular Landscape and Transcriptome Network in Viral Myocarditis by Single-Cell RNA Sequencing

“…Similarly, three transcripts, Apoe , Tgfbi, and Mfap4, were found interesting in cluster 6. They mediate regulation of T cell and macrophage functions, including inflammation and oxidative stress 44 , cardiac fibrosis in concert with Postn 24 , and ventricular remodeling and cardiac function, respectively 45 . As to cluster 8, we noted that a few genes were uniquely expressed with varied functions.…”

Identification of candidate biomarkers and therapeutic agents for heart failure by bioinformatics analysis

“…Experiments show that expression of FAP (fibroblast activation protein alpha) [66], THBS4 [67], CD27 [68], LEF1 [69], CTHRC1 [70], ESR1 [71], CXCL9 [72], SERPINA3 [73], TRPC4 [74], F13A1 [75], PIK3C2A [76], KCNIP2 [77] and GPR4 [78] contributed to myocardial infarction. MFAP4 [79], ALOX15 [80], COL1A1 [81], APOA1 [82], PDE5A [83], CX3CR1 [84], THY1 [85], GREM1 [86], FMOD (fibromodulin) [87], NPPA (natriuretic peptide A) [88], LTBP2 [89], LUM (lumican) [90], IL34 [91], NRG1 [92], CXCL14 [93], CXCL10 [94], ACE (angiotensin I converting enzyme) [95], CFTR (ystic fibrosis transmembrane conductance regulator) [96], S100A8 [97], S100A9 [97], HP (haptoglobin) [98] [162], Zhang et al [163] and Chen et al [164] study indicated that the expression of CCL22, CCR1, FPR1, KNG1, CRISPLD2, CD38 and GPRC5A were linked with progression of ischemic heart disease. Li et al [165] showed that STEAP3 expression can be associated with cardiac hypertrophy progression.…”

“…Experiments show that expression of FAP (fibroblast activation protein alpha) [66], THBS4 [67], CD27 [68], LEF1 [69], CTHRC1 [70], ESR1 [71], CXCL9 [72], SERPINA3 [73], TRPC4 [74], F13A1 [75], PIK3C2A [76], KCNIP2 [77] and GPR4 [78] contributed to myocardial infarction. MFAP4 [79], ALOX15 [80], COL1A1 [81], APOA1 [82], PDE5A [83] [154], OSMR (oncostatin M receptor) [155] and IL15RA [156] are involved in development of obesity, but these genes might be key for progression of HF. CTSG (cathepsin G) is a protein coding gene plays important roles in aortic aneurysms [157].…”