Prevention of Cardiac Dysfunction Development by a Methanocarba Adenosine Monophosphonate Derivative

Accumulating evidence supports a therapeutic role of purinergic signaling in cardiac diseases. Previous studies showed that MRS2339, a charged methanocarba derivative of 2‐Cl‐adenosine monophosphate, is efficacious in animal models of heart failure when infused systemically. However, MRS2339 lacks oral bioavailability as a nucleoside 5’‐phosphate derivative and is subject to hydrolysis in vivo leading to the inactive nucleoside MRS1873. We now test the hypothesis that uncharged adenine nucleoside phosphonates, suitable as oral agents with a hydrolysis‐resistant phospho moiety, can prevent the development of cardiac dysfunction in a post‐infarction ischemic or pressure overloaded heart failure model. Of the diester‐masked uncharged phosphonates evaluated, MRS2978 but not MRS4074, was efficacious in preventing cardiac dysfunction with improved left ventricular (LV) fractional shortening (FS increased from 21±0.79% with vehicle (N=13) to 25.1±0.63% with MRS2978 (N=11), P<0.05) and with preservation of LV wall thickness when administered orally at onset of ischemic heart failure (within 24h after left anterior descending artery (LAD) ligation). MRS2925, the charged, unmasked analog of MRS2978, was able to prevent heart dysfunction only when it was infused subcutaneously; its oral gavage was not efficacious. In the established heart failure models caused either by LAD ligation or transverse aortic constriction (TAC), orally administrated MRS2978 (4 weeks after LAD ligation or 3 weeks after TAC), but not MRS2925, could partially restore cardiac dysfunction by increasing the FS in both ischemic (from 19.7±0.95% with vehicle (N=18) to 26.1±1.37% with MRS2978 (N=11), P<0.05) and pressure overload (FS from 17.5±0.76% with vehicle(N=9) to 23.7±1.25% with MRS2978 (N=10), P<0.05) heart failure models. MRS2978 was orally bioavailable (57–75%F) and highly stable in human, mouse and rat plasma, with 96–100% remaining after 2 h. MRS2925 could be formed from hydrolysis of MRS2978 in vivo, but as a minor metabolite (only 10%), suggesting that the effects of MRS2978 are not dependent on the MRS2925. Either MRS2978 or MRS2925, combining with 2me‐SATP, was capable of activating cardiac myocyte eNOS, consistent with myocyte eNOS activation as a mechanism for the salutary effect of these two phosphonates nucleotides. These data demonstrated the ability of oral therapy with MRS2978 to treat heart failure, both at the inception of heart failure for prevention and after the development of heart failure as a rescue. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .