Work

Prelamin A accumulation overlaps increased vascular calcification in peripheral artery disease and regulates vascular smooth muscle cells mineralization in diabetes mellitus

Year: 2026

Type: article

Abstract: This study investigated the mechanistic intersection between aging, diabetes mellitus (DM), and prelamin A accumulation in vascular calcification (VC) progression in patients with peripheral arterial disease (PAD) undergoing lower limb amputation. Arterial segments were collected from amputated PAD patients with (PAD+DM, n=10) and without DM (PAD, n=8), as well as from non-vascular amputated patients (CTRL, n=3). Additional in vivo and in vitro experiments were conducted to investigate early-stages of VC and the impact of insulin resistance on prelamin A accumulation and ZMPSTE24 expression. PAD and PAD+DM patients exhibited greater VC than CTRL patients. Prelamin A accumulation was higher in PAD (6.3±5.0%) and PAD+DM (10.9±6.4%) than in CTRL (1.2±1.3%), while ZMPSTE24 expression was lower in PAD (5.2±2.6%) and PAD+DM (3.1±3.2%) than in CTRL (20.0±3.8%), indicating impaired prelamin A processing. Investigation in a murine VC model, aortae from leptin-deficient ob/ob mice showed increased prelamin A accumulation, independently of calcifying stimulation. Increased prelamin A expression was also observed insulin-resistant ob/ob VSMCs, independently of calcifying stimulation. These findings suggest that aging-related mechanisms, such as prelamin A accumulation, may synergistically contribute to VC progression, particularly in diabetic PAD patients. Targeting prelamin A processing may unveil a potential therapeutic approach to mitigate VC and reduce amputation risk in diabetic PAD patients. • Prelamin A accumulation is described as a hallmark of aging and a possible mechanism of vascular calcification progression. • •Prelamin A accumulation overlaps VC in PAD patients with and without DM • •Diabetes mellitus (DM) and insulin resistance accelerate VC progression via mechanisms involving increased prelamin A accumulation. • •Aging mechanisms, including lamin A processing dysregulation, may contribute to increased risk of amputation in PAD, especially in diabetic populations. • •The study suggests that therapeutic strategies targeting prelamin A processing could potentially reduce VC and improve cardiovascular outcome in elderly and diabetic patients.

Source: Atherosclerosis Plus

DOI: 10.1016/j.athplu.2026.01.002