miR-34a Promotes Vascular Smooth Muscle Cell Calcification by Downregulating SIRT1 (Sirtuin 1) and Axl (AXL Receptor Tyrosine Kinase)

Abstract

Objective- Vascular calcification (VC) is age dependent and a risk factor for cardiovascular and all-cause mortality. VC involves the senescence-induced transdifferentiation of vascular smooth muscle cells (SMCs) toward an osteochondrogenic lineage resulting in arterial wall mineralization. miR-34a increases with age in aortas and induces vascular SMC senescence through the modulation of its target SIRT1 (sirtuin 1). In this study, we aimed to investigate whether miR-34a regulates VC. Approach and Results- We found that miR-34a and Runx2 (Runt-related transcription factor 2) expression correlates in young and old mice. Mir34a and Mir34a mice were treated with vitamin D, and calcium quantification revealed that Mir34a deficiency reduces soft tissue and aorta medial calcification and the upregulation of the VC Sox9 (SRY [sex-determining region Y]-box 9) and Runx2 and the senescence p16 and p21 markers. In this model, miR-34a upregulation was transient and preceded aorta mineralization. Mir34a SMCs were less prone to undergo senescence and under osteogenic conditions deposited less calcium compared with Mir34a cells. Furthermore, unlike in Mir34a SMC, the known VC inhibitors SIRT1 and Axl (AXL receptor tyrosine kinase) were only partially downregulated in calcifying Mir34a SMC. Strikingly, constitutive miR-34a overexpression to senescence-like levels in human aortic SMCs increased calcium deposition and enhanced Axl and SIRT1 decrease during calcification. Notably, we also showed that miR-34a directly decreased Axl expression in human aortic SMC, and restoration of its levels partially rescued miR-34a-dependent growth arrest. Conclusions- miR-34a promotes VC via vascular SMC mineralization by inhibiting cell proliferation and inducing senescence through direct Axl and SIRT1 downregulation, respectively. This miRNA could be a good therapeutic target for the treatment of VC.

Sirtuin-1 and Its Relevance in Vascular Calcification

“…Consequently, Sirt1 possesses the characteristic of anti-calcification and plays a key role in perpetuating VC [79]. By the way, microRNA-34a promotes VC by downregulating AXL receptor tyrosine kinase (Axl) and Sirt1, resulting in VSMCs senescence and mineralization [80].…”

The Epigenetic Landscape of Vascular Calcification: An Integrative Perspective

“…Among them, 15 (40.5%) have been confirmed or are suspected to promote or aggravate VC in different scenarios, while 22 (59.5%) protect against VC formation or progression. Direct gene targets have been identified for 14 miRNAs with negative VC regulatory capacity, including miR-29a/29b [14], miR-29b-3p [34], miR-30b [16,47], miR-30c [16], miR-30e [25], miR-34b/34c [29,64], miR-125b [13,22] miR-133a [19], miR-135a [30], miR-182 [42], miR-204 [15,41,50], and miR-205 [21], while few direct targets have been identified for miRNAs with VC enhancement ability (miR-34a [39], miR-128-3p [48], and miR-135a-3p [17]). In the following sections, we describe the clinical features of each VC-regulating miRNA based on their propensity for positive or negative vascular influences.…”

“…In VSMCs, miR-34b/34c has been shown to attenuate VC severity through down-regulating special AT-rich sequence-binding protein 2 (SATB2) and subsequently RUNX2 expression levels [29], while down-regulating miR-34b in VSMCs also leads to enhanced calcification [64]. On the contrary, Badi et al focused on the role of miR-34a in the pathogenesis of VC using miR-34 knockout mice [39]. They found that such genetically manipulated mice receiving vitamin D had less soft tissue and aortic calcification compared to wildtype littermates, and the effect was mediated through miR-34-dependent sirtuin 1 (SIRT1) suppression.…”

Maladaptive neuropathological syndrome of blood vessel aging

“…Не без основания можно говорить о том, что предшественник семейства эффек- торных молекул микро-РНК miR-34a связан с сосудистой кальцификацией и ее стимуляцией. Это, в свою очередь, включает вызванную старением трансдифференцировку клеток гладких мышц сосудов, ингибируя при этом пролиферацию клеток и, таким образом, приводя к минерализации артериальной стенки [39]. Следовательно, клетки гладких мышц сосудов играют решающую роль в старении сосудов и образовании аневризмы восходящей грудной аорты.…”