Inhibition of Type 1 Phosphodiesterse Confers Therapeutic Benefit to Proteinopathy‐based HFpEF in Mice
Authors: Zhang Hanming , Rekhter Mark D. , Wang Xuejun 
Published: June 2021

Heart Failure with preserved Ejection Fraction (HFpEF) has overtaken Heart Failure with reduced Ejection Fraction (HFrEF) and represents more than 50% of heart failure cases, yet no pharmacological therapy with mortality benefits has been identified. Targeted clearance of misfolded proteins by the ubiquitin‐proteasome system (UPS) plays a pivotal role in protein quality control. UPS function insufficiency contributes to HF genesis, making UPS priming a potential therapeutic strategy for treatment of HF. Previously we reported that protein kinase G (PKG) positively regulates cardiac UPS functioning while others showed protein kinase A (PKA) stimulates the proteasome. Thus, we hypothesize that simultaneous activation of PKG and PKA improves cardiac UPS function and thereby benefits HF treatment. We found that myocardial protein and mRNA levels of phosphodiesterase 1 (PDE1), a major cardiac PDE that degrades both PKG and PKA, were markedly elevated in CryABR120G transgenic (tg) mice which are a classic model of cardiac proteinopathy with HFpEF as the major manifestation of its cardiac dysfunction. To test whether PDE1 inhibition primes cardiac UPS and thereby ameliorates cardiac proteotoxicity, we performed cell cultures and mouse in vivo experiments taking advantage of a proven surrogate UPS substrate (GFPdgn) and a bona fide misfolded protein (CryABR120G), which demonstrates that pharmacological PDE1 inhibition significantly improves cardiac UPS performance and enhances degradation of misfolded proteins. We then treated CryABR120G tg mice with PDE1 inhibitor LSN2790158 (3 mg/kg/day × 28 days) or vehicle control via osmotic mini‐pumps, starting at 4 months of age when HFpEF has clearly developed in the tg mice as reflected by significant decreases in left ventricular (LV) end‐diastolic volume, stroke volume, and cardiac output and increases in end‐diastolic LV posterior wall thickness along with unchanged EF (>50%), compared to littermate non‐tg mice. Echocardiography revealed that the PDE1 inhibitor treatment resulted in striking improvement of HFpEF. And Kaplan‐Meier survival analysis shows a significant delay of premature death in the PDE1 inhibition group vs. vehicle‐treated group. Additionally, PDE1 inhibition group showed significant reduction of NP‐40 insoluble but SDS soluble fractions of CryAB that represent a misfolded species of CryAB degraded by the proteasome, suggesting that the cardioprotective effect of PDE1 inhibition is, at least in part, due to enhanced removal of misfolded proteins. Our data provide compelling evidence for the first time that PDE1 inhibition shall be explored as a new therapeutic strategy for HFpEF and heart disease with increased proteotoxic stress.Support or Funding InformationThis work was supported in part by NIH grants HL072166, HL085629, and HL131667 and American Heart Association Predoctoral Fellowship grant 16PRE27790059; the PDE1 inhibitor LSN2790158 was provided by Eli Lilly and CompanyThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.