TY - JOUR
T1 - Chronic in vivo nitric oxide deficiency impairs cardiac functional recovery after ischemia in female (but not male) mice
AU - Bienvenu, Laura A.
AU - Morgan, James
AU - Reichelt, Melissa E.
AU - Delbridge, Lea M.D.
AU - Young, Morag J.
PY - 2017/11/1
Y1 - 2017/11/1
N2 - Nitric oxide (NO) is an important regulator of cardiac function and plays a key role in ischemic cardioprotection. The role of chronic NO deficiency in coordinating ischemic vulnerability in female myocardium has not been established. The aim of this study was to determine the influence of chronic in vivo NO synthase inhibition in modulating ex vivo ischemia-reperfusion responses in female hearts (relative to males). Mice were subjected to L-NAME (L-NG-Nitroarginine-methyl-ester) treatment in vivo for 8 weeks. Cardiac fibrotic, inflammatory and cardiomyocyte Ca2 + handling related gene expression changes were assessed. Hearts were Langendorff-perfused, subjected to 20 min global ischemia with 45 min reperfusion. In response to this moderate ex vivo ischemic insult, hearts derived from L-NAME treated female animals exhibited increased incidence of reperfusion arrhythmias, diastolic abnormality and reduced contractile recovery in reperfusion. This differential response was observed even though baseline performance of hearts from L-NAME treated animals was not different to vehicle controls, myocardial inflammatory and fibrotic indices were similar in males and females and the systolic blood pressure effect of L-NAME administration was equivalent in both sexes. Evaluation of a subgroup of mice with cardiomyocyte specific mineralocorticoid receptor deletion suggests involvement of this receptor in NO-deficiency mediated responses. To examine underlying pre-disposing mechanisms, expression of a panel of candidate genes encoding proteins involved in electromechanical homeostasis (particularly relevant to ischemic challenge) was evaluated in normoxic myocardial tissues from the L-NAME- and vehicle-treated animals. Analysis revealed that L-NAME treatment in females selectively regulated expression of genes related directly and indirectly to cardiomyocyte Ca2 + handling in a manner consistent with destabilization of Ca2 + homeostasis and arrhythmogenesis. Our investigation provides new insight into the role of sustained decrease in NO bioavailability in determining distinctive female cardiac vulnerability to ischemic challenge.
AB - Nitric oxide (NO) is an important regulator of cardiac function and plays a key role in ischemic cardioprotection. The role of chronic NO deficiency in coordinating ischemic vulnerability in female myocardium has not been established. The aim of this study was to determine the influence of chronic in vivo NO synthase inhibition in modulating ex vivo ischemia-reperfusion responses in female hearts (relative to males). Mice were subjected to L-NAME (L-NG-Nitroarginine-methyl-ester) treatment in vivo for 8 weeks. Cardiac fibrotic, inflammatory and cardiomyocyte Ca2 + handling related gene expression changes were assessed. Hearts were Langendorff-perfused, subjected to 20 min global ischemia with 45 min reperfusion. In response to this moderate ex vivo ischemic insult, hearts derived from L-NAME treated female animals exhibited increased incidence of reperfusion arrhythmias, diastolic abnormality and reduced contractile recovery in reperfusion. This differential response was observed even though baseline performance of hearts from L-NAME treated animals was not different to vehicle controls, myocardial inflammatory and fibrotic indices were similar in males and females and the systolic blood pressure effect of L-NAME administration was equivalent in both sexes. Evaluation of a subgroup of mice with cardiomyocyte specific mineralocorticoid receptor deletion suggests involvement of this receptor in NO-deficiency mediated responses. To examine underlying pre-disposing mechanisms, expression of a panel of candidate genes encoding proteins involved in electromechanical homeostasis (particularly relevant to ischemic challenge) was evaluated in normoxic myocardial tissues from the L-NAME- and vehicle-treated animals. Analysis revealed that L-NAME treatment in females selectively regulated expression of genes related directly and indirectly to cardiomyocyte Ca2 + handling in a manner consistent with destabilization of Ca2 + homeostasis and arrhythmogenesis. Our investigation provides new insight into the role of sustained decrease in NO bioavailability in determining distinctive female cardiac vulnerability to ischemic challenge.
KW - Cardioprotection
KW - Heart
KW - Ischemia/reperfusion
KW - Mineralocorticoid receptor
KW - Nitric oxide
KW - Sex
UR - http://www.scopus.com/inward/record.url?scp=85028499729&partnerID=8YFLogxK
U2 - 10.1016/j.yjmcc.2017.08.012
DO - 10.1016/j.yjmcc.2017.08.012
M3 - Article
C2 - 28859848
AN - SCOPUS:85028499729
VL - 112
SP - 8
EP - 15
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
SN - 0022-2828
ER -