Deletion of Kvß1.1 subunit leads to electrical and haemodynamic changes causing cardiac hypertrophy in female murine hearts.

NEW FINDINGS: What is the central question of this study? The goal of this study was to evaluate sex differences and the role of the potassium channel ß1 (Kvß1) subunit in the heart. What is the main finding and its importance? Genetic ablation of Kvß1.1 in females led to cardiac hypertrophy characterized by increased heart size, prolonged monophasic action potentials, elevated blood pressure and increased myosin heavy chain α (MHCα) expression. In contrast, male mice showed only electrical changes. Kvß1.1 binds the MHCα isoform at the protein level, and small interfering RNA targeted knockdown of Kvß1.1 upregulated MHCα. Cardiovascular disease is the leading cause of death and debility in women in the USA, and cardiac arrhythmias are a major concern. Voltage-gated potassium (Kv) channels along with the binding partners; Kvß subunits are major regulators of the action potential (AP) shape and duration (APD). The regulation of Kv channels by the Kvß1 subunit is unknown in female hearts. In the present study, we hypothesized that the Kvß1 subunit is an important regulator of female cardiac physiology. To test this hypothesis, we ablated (knocked out; KO) the KCNAB1 isoform 1 (Kvß1.1) subunit in mice and evaluated cardiac function and electrical activity by using ECG, monophasic action potential recordings and echocardiography. Our results showed that the female Kvß1.1 KO mice developed cardiac hypertrophy, and the hearts were structurally different, with enlargement and increased area. The electrical derangements caused by Kvß1.1 KO in female mice included long QTc and QRS intervals along with increased APD (APD20-90% repolarization). The male Kvß1.1 KO mice did not develop cardiac hypertrophy, but they showed long QTc and prolonged APD. Molecular analysis showed that several genes that support cardiac hypertrophy were significantly altered in Kvß1.1 KO female hearts. In particular, myosin heavy chain α expression was significantly elevated in Kvß1.1 KO mouse heart. Using a small interfering RNA strategy, we identified that knockdown of Kvß1 increases myosin heavy chain α expression in H9C2 cells. Collectively, changes in molecular and cell signalling pathways clearly point towards a distinct electrical and structural remodelling consistent with cardiac hypertrophy in the Kvß1.1 KO female mice.

Duplicate gene enrichment and expression pattern diversification in multicellularity.

The enrichment of duplicate genes, and therefore paralogs (proteins coded by duplicate genes), in multicellular versus unicellular organisms enhances genomic functional innovation. This study quantitatively examined relationships among paralog enrichment, expression pattern diversification and multicellularity, aiming to better understand genomic basis of multicellularity. Paralog abundance in specific cells was compared with those in unicellular proteomes and the whole proteomes of multicellular organisms. The budding yeast, Saccharomyces cerevisiae and the nematode, Caenorhabditis elegans, for which the gene sets expressed in specific cells are available, were used as uni and multicellular models, respectively. Paralog count (K) distributions [P((k))] follow a power-law relationship [Formula in text] in the whole proteomes of both species and in specific C. elegans cells. The value of the constant α can be used as a gauge of paralog abundance; the higher the value, the lower the paralog abundance. The α-value is indeed lower in the whole proteome of C. elegans (1.74) than in S. cerevisiae (2.34), quantifying the enrichment of paralogs in multicellular species. We also found that the power-law relationship applies to the proteomes of specific C. elegans cells. Strikingly, values of α in specific cells are higher and comparable to that in S. cerevisiae. Thus, paralog abundance in specific cells is lower and comparable to that in unicellular species. Furthermore, how much the expression level of a gene fluctuates across different C. elegans cells correlates positively with its paralog count, which is further confirmed by human gene-expression patterns across different tissues. Taken together, these results quantitatively and mechanistically establish enrichment of paralogs with diversifying expression patterns as genomic and evolutionary basis of multicellularity.