PCSK9, A Promising Novel Target for Age-Related Cardiovascular Dysfunction

Csaba Matyas; Eszter Trojnar; Suxian Zhao; Muhammad Arif; Partha Mukhopadhyay; Attila Kovacs; Alexandra Fabian; Marton Tokodi; Zsolt Bagyura; Bela Merkely; Laszlo Kohidai; Eszter Lajko; Angela Takacs; Yong He; Bin Gao; Janos Paloczi; Falk W Lohoff; György Haskó; Wen-Xing Ding; Pal Pacher

doi:10.1016/j.jacbts.2023.06.005

PCSK9, A Promising Novel Target for Age-Related Cardiovascular Dysfunction

JACC Basic Transl Sci. 2023 Sep 13;8(10):1334-1353. doi: 10.1016/j.jacbts.2023.06.005. eCollection 2023 Oct.

Authors

Csaba Matyas^{1

2}, Eszter Trojnar¹, Suxian Zhao¹, Muhammad Arif¹, Partha Mukhopadhyay¹, Attila Kovacs³, Alexandra Fabian³, Marton Tokodi³, Zsolt Bagyura³, Bela Merkely³, Laszlo Kohidai⁴, Eszter Lajko⁴, Angela Takacs⁴, Yong He⁵, Bin Gao⁵, Janos Paloczi¹, Falk W Lohoff⁶, György Haskó⁷, Wen-Xing Ding^{8

9}, Pal Pacher¹

Affiliations

¹ Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA.
² Department of Medical Imaging, Medical School, University of Pécs, Pécs, Hungary.
³ Heart and Vascular Center, Semmelweis University, Budapest, Hungary.
⁴ Department of Genetics, Cell and Immunobiology, Semmelweis University, Budapest, Hungary.
⁵ Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA.
⁶ Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA.
⁷ Department of Anesthesiology, Columbia University, New York, New York, USA.
⁸ Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA.
⁹ Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA.

Abstract

Cardiovascular diseases (CVDs) are the leading cause of death among elderly people. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an important regulator of cholesterol metabolism. Herein, we investigated the role of PCSK9 in age-related CVD. Both in humans and rats, blood PCSK9 level correlated positively with increasing age and the development of cardiovascular dysfunction. Age-related fatty degeneration of liver tissue positively correlated with serum PCSK9 levels in the rat model, while development of age-related nonalcoholic fatty liver disease correlated with cardiovascular functional impairment. Network analysis identified PCSK9 as an important factor in age-associated lipid alterations and it correlated positively with intima-media thickness, a clinical parameter of CVD risk. PCSK9 inhibition with alirocumab effectively reduced the CVD progression in aging rats, suggesting that PCSK9 plays an important role in cardiovascular aging.

Keywords: NASH; PCSK9; cardiovascular aging; heart failure; nonalcoholic steatohepatitis; transcriptomics.