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The BMP4/BMPRII-BMPRIA axis drives cardiac hypertrophy and fibrosis by cross-regulating cGMP/PKG and p38 pathways

ABSTRACT: The pathological myocardial hypertrophy and interstitial fibrosis that drive adverse cardiac remodeling are hallmark features of hypertrophic cardiomyopathy and represent a common terminal pathway in various cardiovascular diseases. Bone morphogenetic protein-4 (BMP4) has been implicated in this process, yet its receptor-mediated signaling mechanisms remain incompletely understood. This study aims to elucidate the functional roles of specific BMP receptors—namely BMPRIA and BMPRII—in mediating BMP4-induced pathological cardiac remodeling. Using a combination of transcriptomic profiling in human AC16 cardiomyocytes and validation through pharmacological inhibition, we seek to uncover the downstream signaling pathways responsible for BMP4-driven hypertrophy and fibrosis. The overarching goal is to identify novel receptor-specific therapeutic targets that could enable early intervention or reversal of established cardiac remodeling, potentially through the restoration of cardioprotective cGMP/PKG signaling.

ORGANISM(S): Homo sapiens

PROVIDER: GSE342376 | GEO | 2026/08/30

REPOSITORIES: GEO

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Project description:Abstract Aim: Circulating triglyceride and triglyceride-rich lipoprotein (TRL) accumulation is increasingly recognized as a residual atherosclerotic risk, but their specific effect in cardiac remodeling and heart failure (HF) remain largely unexplored. Here we investigated this issue in Gpihbp1 knockout (KO) mice, which develop severe hyperchylomicronemia due to disruption of intravascular TRL hydrolysis . Methods: Cardiac lipid metabolism and remodeling were evaluated in 10-month-old Gpihbp1 KO mice and wild-type littermates under physiological conditions. Mice were also subjected to transverse aortic constriction (TAC) to evaluate the impact of severe hyperchylomicronemia on pressure overload-induced remodeling and HF. Furthermore, Gpihbp1 KO mice were crossed into Ldlr KO background to study hyperchylomicronemia’s effects on hemorheology and high-fat diet (HFD)-induced cardiac pathology. Results: Untargeted cardiac lipidomics revealed 214 differentially regulated lipid species specifically enriched in glycerophospholipids, fatty acid (FA) and diacylglycerol subclasses. qPCR confirmed down-regulated FA oxidation genes and upregulated glucose utilization genes. Electron microscopy showed swollen mitochondria with fragmented cristae, and RNA-seq demonstrated reduced respiratory-chain gene expression. These derangements culminated in impaired cardiac contractile performance in 10-month-old Gpihbp1 KO mice without inducing hypertrophy or fibrosis. After TAC, Gpihbp1 KO hearts exhibited exaggerated diastolic dysfunction, increased myocyte hypertrophy, and fibrosis. In Gpihbp1/Ldlr double knockout (dKO) mice, reduced erythrocyte deformability and increased whole blood viscosity were observed and worsened post-HFD. Additionally, HFD feeding precipitated significant diastolic impairment, cardiac hypertrophy and fibrosis in dKO mice. Conclusion: Severe hyperchylomicronemia due to GPIHBP1 deficiency sensitizes the heart to pathological remodeling and HF. These findings indicate a potential pathogenic contribution of HTG and TRL accumulation to cardiac disease.

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The BMP4/BMPRII-BMPRIA axis drives cardiac hypertrophy and fibrosis by cross-regulating cGMP/PKG and p38 pathways

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