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

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.