Primary Cilia and Their Role in Acquired Heart Disease

Abstract

Primary cilia are non-motile plasma membrane extrusions that display a variety of receptors and mechanosensors. Loss of function results in ciliopathies, which have been strongly linked with congenital heart disease, as well as abnormal development and function of most organ systems. Adults with congenital heart disease have high rates of acquired heart failure, and usually die from a cardiac cause. Here we explore primary cilia’s role in acquired heart disease. Intraflagellar Transport 88 knockout results in reduced primary cilia, and knockout from cardiac endothelium produces myxomatous degeneration similar to mitral valve prolapse seen in adult humans. Induced primary cilia inactivation by other mechanisms also produces excess myocardial hypertrophy and altered scar architecture after ischemic injury, as well as hypertension due to a lack of vascular endothelial nitric oxide synthase activation and the resultant left ventricular dysfunction. Finally, primary cilia have cell-to-cell transmission capacity which, when blocked, leads to progressive left ventricular hypertrophy and heart failure, though this mechanism has not been fully established. Further research is still needed to understand primary cilia’s role in adult cardiac pathology, especially heart failure.

Tubular obstruction induced polycystin upregulation is pro-fibrotic and induced a severe cystic phenotype in adult mice with autosomal dominant polycystic kidney disease: the coexistence of polycystin loss and gain function in ADPKD

“…Primary cilium is a no-motile, microtubule-based organelle protruding from cell membrane and acts as a senser transducing external signals into cells to control a variety of biological processes (16). Mutations in ciliary genes are involved in the pathology of many organs (17, 18). Recent studies showed that primary cilia play an important role in organ fibrosis (19).…”

Functions of cilia in cardiac development and disease

“…Motile cilia are found at the embryonic node (Alten et al., 2012 ), brain ventricles (Olstad et al., 2019 ), oviducts (Shuiqiao Yuan et al., 2021 ), and airway epithelium (Shah et al., 2009 ). The motile cilia axoneme usually has a 9 + 2 arrangement of microtubules, equipped with dynein arms and radial spokes, which generate beats via dynein arm‐driven adenosine triphosphate (ATP) hydrolysis, to produce fluid movement or propel gametes (Figure 1b ; Hale & Sadoshima, 2022 ; Hjeij et al., 2014 ; Koefoed et al., 2014 ; Reiter & Leroux, 2017 ). However, node motile cilia are an exception because they lack the central microtubule pair and radial spokes (9 + 0 with dynein arms) but can generate rotational movement that results in fluid flow (Figure 1b ; Huang et al., 2009 ; Ishikawa, 2017 ; Shinohara et al., 2015 ).…”

“…Of these cilia‐regulated pathways, several are known to be important for cardiac development (Gabriel et al., 2021 ). Defects in cilia structure and aberrant signaling via the cilium result in a variety of cilia‐associated diseases, collectively known as ciliopathies (Baker & Beales, 2009 ; Hale & Sadoshima, 2022 ; Long & Huang, 2019 ; Reiter & Leroux, 2017 ; Toomer et al., 2019 ). There are nearly 200 distinct ciliopathies (Rao Damerla et al., 2014 ).…”

“…Primary cilia play a crucial role in cell differentiation and embryonic development (May et al., 2021 ). Disorders linked to primary cilia have been identified across various organ systems (Hale & Sadoshima, 2022 ). Our understanding of the role of primary cilia in heart development is still in its infancy, but there is an increasing recognition of primary cilia as important biomechanical and molecular regulators of cardiac development (Toomer et al., 2019 ).…”