Genetic deletion of soluble epoxide hydrolase provides cardioprotective responses following myocardial infarction in aged mice

An aged human heart tissue model showing age-related molecular and functional deterioration resembling the native heart

“…In animal studies perfusion with EETs improved recovery following RI and reduced infarct size [83][84][85] . Consistent with these results, genetic deletion of epoxide hydrolases or use of EHIs have been shown effective in improving LV pressure, decreasing infarct size and fibrosis, and reducing cardiomyocyte death [59][60][61]86,87 However, recently Jameison et al, has shown that the protective effect of genetic deletion of soluble epoxide hydrolase was impaired in 16-month-mice, compared to 3-monthold ones upon myocardial infarction 88 . Similar to in vivo results, effect of EHI was impaired in our stiff human-origin in vitro aged tissue models upon RI mimicking stress.…”

“…An important age-related alteration in cardiovascular physiology is the impaired stress response mechanism of cardiomyocytes and the related reduced effect of therapeutics 10,13,14,82 . Therefore, an aged disease model should reflect these important changes.…”

“…With advanced age, cardiomyocytes are reported to enter senescence as identified with an increase in p21 and p53 expression levels at later ages 5,11 and a related lipofuscin granule presence was observed in the aged heart 12 . Pharmacologically, Jamieson et al have shown that soluble epoxide hydrolase deletion had a protective effect on 3-month-old mice following MI, however, this protective effect was significantly impaired in 16-month-old mice 13 . Similarly, other studies showed that pharmacological effects of various drugs such as adrenaline 14 , isoproterenol, propranolol, and salbutamol 10,15 were reduced in individuals older than 70, showing the crucial role of aging in heart physiology and pathophysiology.…”

Mitochondrial Dysfunction and Inflammaging in Heart Failure: Novel Roles of CYP-Derived Epoxylipids

“…The gene encoding sEH, Ephx2 , is the primary enzyme metabolizing PUFA epoxides resulting in the formation of respective diol metabolites via the addition of a water molecule [ 182 , 183 ]. Novel pharmacological approaches that selectively inhibit sEH have evolved as clinical tools in various cardiovascular diseases, including hypertension, cerebral ischemia, cardiac ischemia, cardiac hypertrophy, myocardial infarction and atherosclerosis [ 202 , 203 , 204 , 205 , 206 , 207 ]. Pharmacological sEH inhibition is demonstrated to improve both LV diastolic and systolic function and attenuate myocardial remodeling in established HF [ 188 , 208 , 209 ].…”

“…Although the exact mechanisms of how epoxylipids regulate cardiac function are not fully understood, accumulating data suggest mitochondria-targeted effects are an important component of their cardioprotective properties [ 203 , 212 , 238 ]. Numerous in vivo and ex vivo studies demonstrate sEH inhibition or treatment with epoxylipids improve LV functional recovery in murine hearts following ischemia-reperfusion injury protecting mitochondrial function and ultrastructure [ 181 , 206 , 225 , 238 , 239 , 240 , 241 ]. Previously, we reported hearts perfused with UA-8 (13-(3-propylureido) tridec-8-enoic acid) a synthetic dual-action compound possessing EET mimetic and sEH inhibitory properties, improved post-ischemic contractile function and reduced infarct size following ischemia-reperfusion injury.…”