Sex-specific phenotypic changes in the hearts of Crip1-deficient mice

Jorge Duque Escobar (Hamburg)1, M. Möhlmann (Hamburg)1, O. Schweigert (Hamburg)1, T. Zeller (Hamburg)1

1Universitäres Herz- und Gefäßzentrum Hamburg Klinik für Kardiologie Hamburg, Deutschland


Hypertension profoundly contributes to CVD which is the leading cause of death worldwide and increases the risk for stroke, renal or cerebral events. It has been also acknowledged that there are sex-specific differences between men and women in the development of hypertension. In a large-scale population-based transcriptomic analysis, our group identified cysteine-rich protein 1 (CRIP1) in human monocytes, which is strongly associated with changes in blood pressure (BP). CRIP1 has previously been described in the context of cardiac development and function, and its expression is increased in monocytes of a mouse model of hypertension. Recently, CRIP1 has been implicated as a regulator of epicardial epithelial-to-mesenchymal transition and affects genes encoding extracellular matrix (ECM) proteins in an epicardial cell culture model.

The aim of this study was to investigate sex-specific changes in the hearts of Crip1-deficient mice that may contribute to the pathogenesis of hypertension and CVD.

Material and Methods

25-week-old mice (strain Bl6J) with Crip1-/- (KO) and wild-type (WT) genotypes were sacrificed. Hearts were used for either immunohistological analysis or gene expression analysis. Tibia length was measured using a caliper. Gene expression analysis of gene clusters potentially affected by Crip1 and sex (cardiac genes, cytoskeleton, fetal gene program, fibrosis, and inflammation) was performed by RT-qPCR. Wheat germ agglutinin (WGA) and pricosirius red staining were used for immunohistological analysis of cardiomyocyte (CM) size and collagen.

Regarding fertility, body weight, behavior, and the ratio of heart weight to body weight (HW/BW) or to tibia length (HW/TL) Crip1-/- mice did not differ phenotypically from their WT littermates. Gene expression analysis of the heart revealed several genes that were significantly altered in KO mice compared to WT mice. In addition, there were significant differences between male and female KO mice, with fibrotic (Col1a1, Col2a1, Col3a1, Postn, Mmp2, Mmp14, Timp1, Timp3) and cytoskeletal (Actb, Tagln, Tpm2, Tuba1b, Tubb2b, Vim) genes being the most affected. In histological analysis, immunofluorescent WGA-stained heart sections showed a significant difference in cardiomyocyte diameter only in Crip1-deficient male mice compared to wild-type littermates. Staining of collagen content in the heart did not show differences between genotypes and sex.

Depletion of Crip1 resulted in several changes in the expression of fibrotic and cytoskeletal genes, which were highly sex-dependent. Interestingly, only in the male mice did the size of the CM differ from that of the wild-type controls. These results provide a deeper insight into the potential role of sex-specific cardiac Crip1 in the pathogenesis of hypertension and CVD.

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