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Interleukin-8 mediated cellular crosstalk drives hypertrophic cardiomyopathy in LZTR1 2 deficiency

ABSTRACT: LZTR1 deficiency causes Noonan syndrome (NS) and is associated with the manifestation of severe and early-onset hypertrophic cardiomyopathy (HCM). Although paracrine communication is thought to play a critical role in cardiac pathology, little is known about the underlying pathomechanism leading to the development of HCM and cardiac fibrosis in NS. In the present study, we used 2D and 3D iPSC models with LZTR1 deficiency to dissect the impact of non-cardiomyocytes in the development of NS-associated HCM and uncovered a cytokine mediated intercellular crosstalk, predominantly activated in the disease state, as a major driver of cardiac hypertrophy and cardiac fibrosis. We showed that cardiac fibroblast-specific secretion of interleukin-8 induces a fibrosis-related signature and potentiates cardiomyocyte 45 hypertrophy. Importantly, inhibition of IL-8 signaling reversed the pathological effects in 46 cardiac fibroblasts and cardiomyocytes and may serve as a novel therapeutic option for the 47 treatment of NS-associated HCM.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Heart, Cardiac Ventricle Fibroblast, Pluripotent Stem Cell, Cardiac Muscle Myoblast, Cardiac Endothelial Cell

DISEASE(S): Familial Hypertrophic Cardiomyopathy

SUBMITTER: Christof Lenz

LAB HEAD: Christof Lenz

PROVIDER: PXD053691 | Pride | 2026-04-01

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20200217_UP_HOMSA_BOSTA_iRT_cRAP.fasta	Fasta
	2021_65_M_Pavez-Giani_DIA_CardiacFibroblasts_ConditionSetup.xls	Xls
	2021_65_M_Pavez-Giani_DIA_Cardiomyocytes_ConditionSetup.xls	Xls
	2021_65_M_Pavez-Giani_DIA_EndothelialCells_ConditionSetup.xls	Xls
	20220217_215325_2021_65_M_Pavez-Giani_DIA_CardiacFibroblasts.sne	Other

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Project description:Background: Hypertrophic cardiomyopathy (HCM) is an autosomal dominant genetic disorder, characterized by cardiomyocyte hypertrophy, cardiomyocyte disarray and fibrosis, which has a prevalence of ~1:200-500 and predisposes individuals to sudden death and heart failure. The mechanisms through which diverse HCM-causing mutations cause cardiac dysfunction remain mostly unknown and their identification may reveal new therapeutic avenues. MicroRNAs have emerged as critical regulators of gene expression and disease phenotype in various pathologies. We explored whether miRNAs could play a role in HCM pathogenesis and offer potential therapeutic targets. Methods and Results: Using high-throughput miRNA expression profiling and qPCR analysis in two distinct mouse models of HCM, we found that miR-199a-3p expression levels are upregulated in mutant mice compared to age- and treatment-matched wild-type mice. We also found that miR-199a-3p expression is enriched in cardiac non-myocytes compared to cardiomyocytes. When we expressed miR-199a-3p mimic in cultured primary cardiac non-myocytes and analyzed the conditioned media by proteomics, we found that several ECM proteins (e.g., TSP2, FBLN3, COL11A1, LYOX) were differentially expressed. We confirmed our proteomics findings by qPCR analysis of selected mRNAs and demonstrated that miR-199a-3p mimic expression in cardiac non-myocytes drives upregulation of ECM genes including Tsp2, Fbln3, Pcoc1, Col1a1 and Col3a1. To examine the role of miR-199a-3p in vivo, we inhibited its function using lock-nucleic acid (LNA)-based inhibitors (antimiR-199a-3p) in an HCM mouse model. Our results revealed that progression of cardiac fibrosis is attenuated when miR-199a-3p function is inhibited in mild-to-moderate HCM. Finally, guided by computational target prediction algorithms, we identified mRNAs Cd151 and Itga3 as direct targets of miR-199a-3p and have shown that miR-199a-3p mimic expression negatively regulates AKT activation in cardiac non-myocytes. Conclusions: Altogether, our results suggest that miR-199a-3p may contribute to cardiac fibrosis in HCM through its actions in cardiac non-myocytes. Thus, inhibition of miR-199a-3p in mild-to-moderate HCM may offer therapeutic benefit in combination with complementary approaches that target the primary defect in cardiac myocytes.

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Interleukin-8 mediated cellular crosstalk drives hypertrophic cardiomyopathy in LZTR1 2 deficiency

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