How does LRP6 (Ser1490) regulate myocardial paracrine signaling to suppress pressure overload-induced cardiac fibrosis?

1. How does pressure overload lead to pathological cardiac remodeling?

Cardiovascular diseases such as hypertension and valvular heart disease often cause the heart to endure abnormally elevated pressure loads over extended periods, a state known as pressure overload. Persistent mechanical stress triggers a series of adaptive and pathological changes in the heart, with the core pathological processes including compensatory cardiomyocyte hypertrophy, sustained inflammatory responses, and cardiac fibrosis characterized by excessive extracellular matrix deposition. These changes collectively lead to progressive cardiac remodeling, ultimately impairing ventricular diastolic and systolic functions and resulting in heart failure. During this process, various cardiac cells (e.g., cardiomyocytes, fibroblasts, immune cells) interact through complex paracrine signaling networks. A deeper understanding of how cardiomyocytes regulate the surrounding microenvironment through secreted signaling molecules under pressure overload, particularly in counteracting fibrosis, is crucial for developing new myocardial protection strategies.

2. What role does the LRP6 receptor play in cardiac homeostasis and stress responses?

Low-density lipoprotein receptor-related protein 6 (LRP6) is a key co-receptor in the Wnt/β-catenin canonical signaling pathway and also functions in non-canonical Wnt signaling. It is not only essential during embryonic development but also widely involved in the regulation of proliferation, differentiation, metabolism, and apoptosis in adult tissues. Previous studies have shown that LRP6 has protective effects in the heart: cardiomyocyte-specific knockout of LRP6 impairs autophagy and fatty acid metabolism, leading to cardiac dysfunction. Additionally, LRP6 can mitigate myocardial ischemia-reperfusion injury by inhibiting apoptosis. These findings suggest that LRP6 may be an important endogenous protective molecule for maintaining cardiac homeostasis and combating stress-induced damage.

3. Can cardiomyocyte-specific LRP6 overexpression improve pressure overload-induced cardiac fibrosis?

To investigate the specific role of LRP6 in pressure overload-induced cardiac remodeling, the research team constructed a cardiomyocyte-specific, tamoxifen-inducible LRP6 overexpression mouse model and performed transverse aortic constriction (TAC) surgery to simulate pressure overload.

The experimental results showed that, compared to the control group, cardiomyocyte-specific LRP6 overexpression significantly improved cardiac systolic and diastolic functions in mice after TAC surgery. More importantly, LRP6 overexpression effectively suppressed pressure overload-induced pathological cardiomyocyte hypertrophy and myocardial interstitial fibrosis. This finding directly demonstrates that enhancing LRP6 signaling in cardiomyocytes can counteract adverse cardiac remodeling caused by pressure overload, with a clear effect on inhibiting fibrosis.

4. What molecular mechanism does LRP6 employ to inhibit cardiac fibrosis?

Mechanistic exploration revealed a unique pathway through which LRP6 exerts its anti-fibrotic effects. The study found that under pressure overload, cardiomyocytes secrete more Wnt family ligands, particularly Wnt5a and Wnt11. These paracrine Wnt ligands activate cardiac fibroblasts, promoting their proliferation and transformation into myofibroblasts, thereby driving excessive synthesis and deposition of extracellular matrix—the fibrosis process.

LRP6 acts as a "molecular brake" in this process. Research indicates that LRP6 can bind to the lysosomal protease cathepsin D (CTSD). This interaction facilitates the intracellular uptake and/or degradation of Wnt5a and Wnt11 by LRP6, reducing the effective concentration of these pro-fibrotic signaling molecules in the extracellular microenvironment and blocking their activation of fibroblasts. Clinical correlation analysis further supports this mechanism: in patients with dilated cardiomyopathy and hypertension, loss-of-function mutations in LRP6 or CTSD are associated with higher expression of Wnt5a and Wnt11 in cardiac tissues and worse cardiac function.

5. What is the application value of the LRP6 (Ser1490) phospho-specific antibody in related research?

The activity and function of LRP6 are finely regulated by the phosphorylation of multiple sites in its intracellular domain. Among these, phosphorylation at Ser1490 is a key event in LRP6 activation and downstream signaling. The phosphorylation state of this site directly affects LRP6's conformation, stability, and interactions with downstream signaling molecules.

Therefore, a highly specific LRP6 (Ser1490) recombinant rabbit monoclonal antibody is indispensable for in-depth investigations of LRP6 functional regulation:

1. Assessing LRP6 activation status: In pressure overload models or drug intervention studies, this antibody can be used to directly detect LRP6 activation levels (p-Ser1490) in cardiomyocytes, correlating receptor activation states with cardiac phenotypic improvements.

2. Elucidating upstream regulatory mechanisms: Using this antibody, researchers can study which upstream kinases or signaling pathways (e.g., specific stress signals) regulate LRP6 Ser1490 phosphorylation under pressure overload, thereby identifying the molecular switches that initiate LRP6's protective effects.

3. Validating receptor activator efficacy: In the development of small-molecule LRP6 activators, detecting increased p-LRP6 (Ser1490) levels serves as one of the most direct pharmacodynamic evidences of successful target receptor activation.

6. Summary and Future Perspectives

This study systematically elucidates a novel mechanism by which the cardiomyocyte LRP6 receptor inhibits cardiac fibrosis under pressure overload through binding to CTSD and promoting the degradation of pro-fibrotic paracrine factors Wnt5a/11, thereby improving cardiac function. This discovery not only reveals a new endogenous anti-fibrotic pathway in the heart but also provides a solid theoretical foundation for developing LRP6 as a therapeutic target for pathological cardiac remodeling (e.g., hypertensive heart disease, valvular heart disease-induced heart failure). In the future, using tools such as the LRP6 (Ser1490) recombinant rabbit monoclonal antibody to further dissect the activation regulatory network of LRP6 and identifying or designing specific LRP6 receptor agonists based on this knowledge may open new therapeutic avenues for clinically preventing and treating pressure overload-induced heart failure.

7. Which manufacturers provide the LRP6 (Ser1490) recombinant rabbit monoclonal antibody?

Hangzhou Starter Biotechnology Co., Ltd. has independently developed the "Phospho-LRP6 (Ser1490) Recombinant Rabbit Monoclonal Antibody" (product name: Phospho-LRP6 (Ser1490) Recombinant Rabbit mAb (S-1489-86), catalog number: S0B1241). This product is a high-performance tool for detecting receptor activation in the Wnt/β-catenin signaling pathway, featuring exceptional phospho-site specificity, sensitivity, and stability. Developed using recombinant rabbit monoclonal antibody technology, it has been rigorously validated across multiple platforms, including Western Blot (WB) and immunofluorescence (IF), and holds critical application value in fields such as developmental biology, stem cell self-renewal, and tumorigenesis mechanisms.

Professional technical support: We provide comprehensive product technical documentation, including examples of phosphorylation time courses under Wnt3a stimulation, recommendations for correlating total LRP6 and downstream β-catenin protein levels, and specialized technical consultations, fully assisting customers in achieving precise and reliable discoveries in developmental biology and tumor signaling research.

Hangzhou Starter Biotechnology Co., Ltd. is committed to providing high-quality, high-value biological reagents and solutions for global innovative pharmaceutical companies and research institutions. For more details about the "Phospho-LRP6 (Ser1490) Recombinant Rabbit Monoclonal Antibody" (catalog number S0B1241) or to request a sample test, please feel free to contact us.

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