Effecting around 2% of all adults in western countries, heart failure is the leading reason for hospitalization and mortality in elderly individuals, despite modern medical treatment. In the pathophysiology of heart failure, cardiac hypertrophy plays an important role, but its molecular mechanisms are yet to be completely understood. 

We previously identified components of the striatin-interacting phosphatase and kinase (STRIPAK) complex, like Mysocape/STRIP2 as regulators of cardiac hypertrophy in vivo and in vitro, controlling the Calcineurin-NFAT(Cn-NF)-signaling pathway. Now, we suggest that the striatin-interacting protein 1 (STRIP1), a core member of STRIPAK and paralog gene of STRIP2, would play a complementary role in regulating cardiac hypertrophy. Unlike STRIP2, STRIP1 thereby is abundant in various rodent and human tissues and also in heart and skeletal muscle. In neonatal rat ventricular cardiomyocytes (NRVCM), adenoviral STRIP1 overexpression results in decreased mRNA-expression of hypertrophy markers from the “fetal gene program”, including NPPA, NPPB while the regulator of calcineurin (RCAN1.4) was significantly downregulated, when compared to AdLacZ treated control-NRVCM (p ≤ 0,01; n=3). In contrast, NPPA-mRNA-expression was significantly increased in siRNA induced STRIP1-Knockdown (KD) cardiomyocytes (p ≤ 0,01; n=3) compared to siNegative-Control-KD NRVCM. 

In Co-Immunoprecipitation experiments in NRVCM, fishing for STRIP1, STRIPAK-members STRIP2 and MST4 were identified as direct interacting partners of STRIP1 confirming that STRIPAK is also present in the heart. By immunofluorescence staining for STRIP1 and its interactors, we could confirm the colocalisation of STRIP1 with STRIP2/MST4 in the interspaces of myofibrills of adult ventricular rat cardiomyocytes and in the perinuclear area of adult and neonatal cardiomyocytes. A nuclear accumulaltion of STRIP1 was observed in cardiac myocytes, colocalising with Nucleolin, a nucleolar-specific protein. 

STRIP1 was stained in mouse cardiac tissue, revealing an additional localization at the z-discs and area composita, suggesting a possible role in force transmission and strain sensing at the intercalated discs.

Following STRIP1-KD in NRVCM, a significant increase in MST4-phosphorylation on T174, which is associated with autophosphorylation and activation of this main STRIPAK kinase, was observed (p ≤ 0,001; n=3). Since we can also show, that activation or artificial overexpression of MST4 can stimulate hypertrophy in NRVCM, we propose a STRIPAK dependent regulation of cardiac hypertrophy is involving both MST4 and STRIP1/STRIP2.

In vivo, morpholino mediated STRIP1-KD in zebrafish resulted in cardiac hypertrophy and heart failure with pericardial effusion 72h post fertilization. And emphasizing a human relevance in disease, human cardiac biopsy samples of patients with dilated/ischemic cardiomyopathy showed significant downregulation of STRIP1 protein compared to non-failure control (p ≤ 0,01; n=10).

Taking together, we identified the STRIPAK-member STRIP1 as a novel cardiac nucleolar protein, locating also to sarcomeres and intercalated discs, regulating cardiac hypertrophy possibly via STRIP1/MST4 interaction, and that is downregulated in human cardiomyopathy.