All experiments involving animals conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication 8th edition, update 2011) and were approved by the Institutional Animal Care and Use Committee of the University of Texas Southwestern Medical Center. The studies were in compliance with all ethical regulations. C57BL/6N mice were used for wild-type (WT) studies. Tetracycline responsive elements (TRE)-Xbp1s mice were crossed with mice harbouring tetracycline transactivator (tTA) transcription factor driven by α-myosin heavy chain promoter (αMHC-tTA) to generate mice with cardiomyocyte-specific inducible overexpression of Xbp1s (Xbp1s TG) as previously described10 (link). iNOS knockout mice (Nos2−/−, B6.129P2-Nos2tm1Lau/J) were purchased from Jackson Laboratory (Bar Harbor, Maine) to establish an in-house colony. ZSF1-obese (ZSF1-LeprfaLeprcp/Crl, strain code 378) and Wistar-Kyoto (WKY) rats were obtained from Charles River Laboratories (Wilmington, Massachusetts). Male adult (8/12 week-old) mice were used in the experiments. Analyses in rats were carried out when the animals reached 20 weeks of age. Mice and rats were maintained on a 12-hour light/dark cycle from 6 AM to 6 PM and had unrestricted access to food (#2916, Teklad for CHOW groups and D12492, Research Diet Inc. for the HFD groups) and water. N[w]-nitro-l-arginine methyl ester (L-NAME; 0.5 g/L, Sigma Aldrich) was supplied in the drinking water for the indicated periods of time, after adjusting the pH to 7.4. L-N6-(1-iminoethyl)lysine (L-NIL, Cayman Chemical) was administered intraperitoneally (i.p.) at a dose of 80 mg/kg body weight twice a day for three days. Transverse aortic constriction (TAC or severe TAC, sTAC) was surgically induced as previously described24 (link).