Upregulating the heme oxygenase system suppresses left ventricular hypertrophy in adult spontaneously hypertensive rats for 3 months.
BACKGROUND
Aldosterone and phospholipase C (PLC) stimulate nuclear factor-kappaB (NF-kappaB) and activating-protein (AP-1), causing fibrosis and hypertrophy. Besides harboring binding sites for NF-kappaB and AP-1, heme oxygenase (HO-1) generates cytoprotective products, including bilirubin and ferritin. The multifaceted interaction between HO-1 and aldosterone-PLC profibrotic axis in cardiac hypertrophy of spontaneously hypertensive rats (SHR) was studied.


RESULTS
HO-1 was induced with hemin or blocked with chromium mesoporphyrin (CrMP). The study groups included: (A) controls (SHR, WKY, and SD), (B) SHR+hemin, (C) SHR+hemin+CrMP, (D) SHR+CrMP, and (E) SHR+vehicle. Histological and morphological/morphometrical, quantitative reverse transcription-polymerase chain reaction, Western blot, enzyme immunoassay, and spectrophotometric assays were used to assess the effect of the HO system on cardiac hypertrophy. Hemin therapy evoked a 3-month enduring cardioprotection in adult SHR by lowering blood pressure, and reducing left-to-right ventricular ratio, left ventricular wall-thickness, and left ventricle-to-body-weight ratio, whereas CrMP exacerbated cardiac fibrosis/hypertrophy. The cardioprotection was accompanied by reduced aldosterone, PLC, inositol-triphosphate, NF-kappaB, AP-1, heme, and 8-isoprostane, a marker of oxidative stress, whereas HO-1, HO activity, cGMP, bilirubin, ferritin, superoxide dismutase, and the total antioxidant capacity were increased. Correspondingly, extracellular matrix/remodeling proteins such as fibronectin, collagen-1, collagen-IV, alongside cardiac histopathological lesions including fibrosis, scarring, muscular-hypertrophy, coronary-arteriolar thickening, and interstitial/perivascular collagen deposition were attenuated.


CONCLUSIONS
Our study unveils sustained cardioprotection by hemin that may have clinical relevance.
Ndisang
Joseph Fomusi
JF
Department of Physiology, University of Saskatchewan College of Medicine, Saskatoon, SK, Canada. joseph.ndisang@usask.ca
Jadhav
Ashok
A
D000367:Age Factors; D000818:Animals; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis*; D006427:Hemin / Q000494:pharmacology / Q000627:therapeutic use; D006973:Hypertension / Q000150:complications / Q000188:drug therapy / Q000201:enzymology*; D017379:Hypertrophy, Left Ventricular / Q000150:complications / Q000188:drug therapy / Q000201:enzymology*; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
D006427:Hemin; D006419:Heme Oxygenase (Decyclizing)