Wednesday, February 5, 2025
2/5/2025
PROJECT SUMMARY Vascular calcification is common in patients with chronic kidney disease (CKD) and contributes to mortality. Calciprotein particles (CPPs) have emerged as a promising therapeutic target. In CKD, excess CPPs build up in the blood and transform into pathogenic forms—primary and secondary CPPs, which have been shown in preclinical studies to cause vascular calcification by inducing inflammation, dysfunction of endothelial cells, and calcification of vascular smooth muscle cells. Whether and how serum CPPs lead to vascular calcification in CKD patients is an important knowledge gap. Our study will help fill this gap by testing the hypothesis that serum CPPs from CKD patients lead to macro-calcification, micro-calcification, and calcification of human vascular smooth muscle cells. Because vascular calcification resembles bone mineralization, agents that inhibit vascular calcification may adversely affect bone formation. By studying the function of vascular cells, our proposal provides mechanistic insight that may serve as a basis for future CPP-related therapies to attenuate vascular calcification without impacting bone health. At a cellular level, vascular smooth muscle cells in arterial media and endothelial cells in the intima play pivotal roles in vascular calcification. Vascular smooth muscle cells undergo osteogenic differentiation, a process that initiates mineralization in the vessel walls; and endothelial cells can regulate this process. Macro- and micro-calcification confer different cardiovascular risks, and studying micro-calcification allows for early detection and intervention. Using our novel methods of measuring serum CPP size and quantity, we will test our hypothesis in 3 aims. Aim 1 will determine the association between serum CPPs and macro-calcification in coronary arteries by leveraging the Chronic Renal Insufficiency Cohort, which has stored serum and assessment of macro-calcification in coronary arteries by computed tomography (n=780). We will measure serum CPP size and quantity in these serum samples. We will also measure serum markers for endothelial function corresponding to nitric oxide production, activation, hemostasis, and inflammation, and determine whether these markers mediate the association between CPPs and calcification. Aim 2 will determine the association between serum CPPs and micro-calcification of aorta in a prospective longitudinal study of 60 patients with CKD stage 4. We will measure serum CPP size and quantity in these patients, and quantify micro-calcification of aorta using 18F-sodium fluoride positron-emission tomography at both baseline and Year 1. Aim 3 will define the effects of CPPs derived from CKD patients on human primary vascular cells. We will generate CPPs from the serum of CKD patients recruited in Aim 2, and test their effects on calcification of human smooth muscle cells, function of endothelial cells, and endothelial- smooth muscle cell paracrine mechanism. We expect that CPPs induce calcification of smooth muscle cells, and endothelial cells exposed to CPPs exacerbate this effect. By defining the effects of serum CPP on vascular calcification, the results will inform the development of future CPP-targeted interventions.
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