Cardiomyocyte DCHS2 Inhibition Protects Against Heart Failure

Loss of cardiomyocytes (CMs) and impaired mitochondrial function are major causes of heart failure (HF). We recently found that cardiac Dachsous Cadherin-Related 2 (DCHS2) is induced in pathological hypertrophy and HF but inhibited by exercise. CM DCHS2 expression in vivo causes pathological hypertrophy while its deletion induces physiological hypertrophy and increases markers of cardiomyogenesis. Whether and how DCHS2 inhibition protects against pathological hypertrophy or HF are unknown. CAS9 knock-in mice were injected with AAV9 carrying scrambled (control) or guide RNA1 (gRNA1) targeting DCHS2 exon 2 together with troponin T-driven Cre and subjected to transverse aortic construction (TAC). 10 weeks after TAC, DCHS2 knockdown (KD) in CMs reduced heart (HW) and lung weight / tibial length (TL) ratios (HW/TL: 11.14±0.76 vs 13.72±0.72 mg/mm, p=0.04, n=6/group), increased fractional shortening (40.67±3.65% vs 28.80±3.51%, p=0.04, n=6/group) and decreased CM size. DCHS2 KD in CMs increased markers of CM proliferation (Ki67 and pHH3, PCM1 double positive cells, all p<0.05) and expression of mitochondrial respiratory chain complexes I-V protein and PGC1α mRNA (all p<0.05) while attenuating TAC-induced disruption of mitochondrial structure and reactive oxygen species production measured by DHE staining. In primary CMs, DCHS2 gene KD by siRNA increased CM proliferation (13.93±1.09% vs 10.11±0.14%, p=0.03, n=6) which was prevented by Yap1 KD (13.93±1.09% in DCHS2 KD vs 7.45±0.89 in DCHS2/Yap1 double KD, p<0.01, n=6). DCHS2 KD also increased mitochondrial oxygen consumption (354.8±25.86 vs 248.2±10.42 pmol/min, p<0.01, n=6) and enhanced expression of mitochondrial biogenesis-related genes as well as mtDNA copy number (all p<0.05). These DCHS2 KD-induced changes were not affected by Yap1 KD but were canceled by KD of either PGC1α or Acadvl, which is essential for very long chain fatty acids oxidation (all p<0.05). DCHS2 pulldown demonstrated that Acadvl directly bound DHCS2 in CMs. In conclusion, DCHS2 inhibition protects against HF through Yap1-dependent cardiomyogenesis and Acadvl-dependent mitochondrial effects.