Biomolecules 2021, 11, 1482. https://doi.org/10.3390/biom11101482 www.mdpi.com/journal/biomolecules Review Biomolecules Orchestrating Cardiovascular Calcification Yin Tintut 1,2,3,4 , Henry M. Honda 1 and Linda L. Demer 1,2,4,5,6, * 1 Department of Medicine, University of California-Los Angeles, Los Angeles, CA 90095, USA; ytintut@mednet.ucla.edu (Y.T.); HHonda@mednet.ucla.edu (H.M.H.) 2 Department of Physiology, University of California-Los Angeles, Los Angeles, CA 90095, USA 3 Department of Orthopaedic Surgery, University of California-Los Angeles, Los Angeles, CA 90095, USA 4 Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA 5 Department of Bioengineering, University of California-Los Angeles, Los Angeles, CA 90095, USA 6 The David Geffen School of Medicine, University of California-Los Angeles, 10833 Le Conte Ave, Los Angeles, CA 90095, USA * Correspondence: ldemer@mednet.ucla.edu; Tel.: +1-(310)-206-2677 Abstract: Vascular calcification, once considered a degenerative, end-stage, and inevitable condi- tion, is now recognized as a complex process regulated in a manner similar to skeletal bone at the molecular and cellular levels. Since the initial discovery of bone morphogenetic protein in calcified human atherosclerotic lesions, decades of research have now led to the recognition that the regula- tory mechanisms and the biomolecules that control cardiovascular calcification overlap with those controlling skeletal mineralization. In this review, we focus on key biomolecules driving the ectopic calcification in the circulation and their regulation by metabolic, hormonal, and inflammatory stim- uli. Although calcium deposits in the vessel wall introduce rupture stress at their edges facing ap- plied tensile stress, they simultaneously reduce rupture stress at the orthogonal edges, leaving the net risk of plaque rupture and consequent cardiac events depending on local material strength. A clinically important consequence of the shared mechanisms between the vascular and bone tissues is that therapeutic agents designed to inhibit vascular calcification may adversely affect skeletal mineralization and vice versa. Thus, it is essential to consider both systems when developing ther- apeutic strategies. Keywords: cardiovascular; calcification; inflammation; lipids; skeletal 1. Introduction Vascular calcification is an ectopic calcification triggered by chronic inflammatory conditions and/or mineral imbalance. Previously considered a degenerative, end-stage, and inevitable condition, it is now recognized as a complex process regulated at the mo- lecular and cellular levels by a wide range of metabolic and hormonal stimuli. It shares many regulatory factors and processes with bone formation in the embryonic skeleton, including both endochondral and/or intramembranous forms of mineralization. As a con- sequence, therapeutic agents designed to inhibit vascular calcification may adversely af- fect skeletal mineralization and vice versa [1]. In this review, we focus on core biomole- cules that regulate the process of calcification in the cardiovascular system. However, there are many more biomolecules involved in vascular calcification that we have not dis- cussed in this review, such as sclerostin, klotho, and microRNA. 2. Forms of Artery Wall Calcium Deposits Arterial calcification consists of calcium phosphate deposits in the forms of hydrox- yapatite [Ca10(PO4)6(OH)2], whitlockite [Ca18Mg2(HPO4)2(PO4)12] [2], octacalcium phos- phate [Ca8(HPO4)2(PO4)4.5H2O], and amorphous calcium phosphate [3]. In skeletal bone, hydroxyapatite is the most abundant mineral form, and whitlockite the second most Citation: Tintut, Y.; Honda, H.M.; Demer, L.L. Biomolecules Orchestrating Cardiovascular Calcification. Biomolecules 2021, 11, 1482. https://doi.org/10.3390/ biom11101482 Academic Editor: Vladimir N. Uversky Received: 18 August 2021 Accepted: 3 October 2021 Published: 7 October 2021 Publisher’s Note: MDPI stays neu- tral with regard to jurisdictional claims in published maps and insti- tutional affiliations. Copyright: © 2021 by the authors. Li- censee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and con- ditions of the Creative Commons At- tribution (CC BY) license (http://crea- tivecommons.org/licenses/by/4.0/).